Parenteral formulations of dopamine agonists

ABSTRACT

This invention relates to stable pharmaceutical compositions for parenteral administration comprising dopamine agonists and peripheral acting agents useful for treatment of metabolic disorders or key elements thereof. The parenteral dosage forms exhibit long stable shelf life and distinct pharmacokinetics.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of international application no.PCT/U.S.09/00268, filed Jan. 14, 2009, which is a continuation-in-partof prior U.S. application Ser. No. 12/144,620, filed Jun. 23, 2008. Thisapplication is also a continuation-in-part of prior U.S. applicationSer. No. 12/144,620, filed Jun. 23, 2008. The application claimspriority under 35 U.S.C. §119 of U.S. provisional application No.61/020,930, filed Jan. 14, 2008 and U.S. provisional application No.60/945,562 filed Jun. 21, 2007. Each of the foregoing applications ishereby incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

This invention relates to pharmaceutical parenteral dosage formulationscomprising dopamine agonists, alone or in combination with peripheralacting agents useful for treatment of metabolic disorders, and toprocesses for preparing such formulations and methods of treatment usingsuch formulations.

BACKGROUND OF THE INVENTION

Dopamine agonists are useful in the treatment of various diseases suchas migraine headache, Parkinson's disease, acromegaly,hyperprolactinemia, prolactinoma, galactorrhea, amenorrhea, andmetabolic disorders. It has been typically preferred to administerdopamine agonists in tablet and capsule forms. Administration ofdopamine agonists via the gut, however, is subject to several problems.

Dopamine agonists absorbed via the gastric or intestinal mucosa of thegastrointestinal (GI) tract, for example, typically undergo extensive“first-pass” metabolism and destruction by the viscera, primarily theliver, resulting in a very small percentage of an administered dosereaching the systemic circulation. First-pass metabolism results frominactivation of orally administered drug in the gut and liver, beforethe drug reaches the systemic circulation for delivery to other organsand tissues of the body. Consequently, oral doses of compounds formedicinal use that are subject to first pass metabolism for medicinaluse must be high enough to account for the substantial initial loss ofdrug, so that sufficient amounts of the drugs reach the systemiccirculation to produce a therapeutic benefit.

Absorption of dopamine agonists via the gastric or intestinal mucosa mayalso be problematic because dopamine agonists and their metabolites maycause undesirable side effects (e.g., nausea, vomiting, abdominal pain,constipation, and diarrhea). The need to use increased dosages toaccount for first-pass metabolism in order to achieve therapeuticeffectiveness increases the probability of undesirable GI side effects.

First-pass metabolism and visceral exposure can be substantially avoidedby parenteral drug dosage forms that provide for administration and thesubstantial absorption of dopamine agonists through a route or routesother than the gastric and/or intestinal mucosa. Parenteral drug dosageforms also beneficially provide a mechanism for reducing the overalltherapeutic dopamine agonist dosage amount, inasmuch as there is nonecessity to overcome first-pass metabolism.

Production of stable parenteral formulations comprising ergot derivativedopamine agonists is particularly challenging, however, because ergotderivatives are extremely labile to light and water. Thus, ergotderivatives must be formulated in a manner that avoids light andprevents hydration.

Further, formulations useful for treating metabolic disorders or the keyelements thereof require production of a particular pharmacokineticprofile that takes into account daily fluctuations in the levels ofvarious hormones. That is, many of the hormones involved in metabolicdisorders exhibit a daily circadian rhythm of fluctuating serum levels.Such hormones include adrenal steroids, e.g., the glucocorticosteroids,notably cortisol, and prolactin, a hormone secreted by the pituitarygland. These daily rhythms provide useful indices for understanding andtreating metabolic diseases. For example, peak concentration ofprolactin occurs at different times of day in lean and fat animals.

The normal daily prolactin level profile of a healthy human is highlyregular and reproducible, characterized by a low and relatively constantday level followed by a sharp night-time peak, returning to a low levelby daytime. See U.S. Pat. No. 5,679,685 the contents of which areincorporated herein by reference. Altering the prolactin profile of asubject having a metabolic disorder or key element thereof to resemblethat of a healthy subject of the same species and sex can providetherapeutic benefit to the subject. Dopamine agonists are useful agentsfor treatment of metabolic disease and/or key elements of metabolicdisease and can be used to reset daily prolactin profiles in subjectswith metabolic disease and/or exhibiting key elements thereof to that ofhealthy humans.

Administration of dopamine agonists can act centrally to readjusttowards “normal” those aberrant neuroendocrine events controllingperipheral metabolism in subjects with metabolic disease. Dopamineagonist therapy thus can impact etiological factors in the developmentand maintenance of metabolic disorders including, but not limited to,those associated with obesity, type 2 diabetes, pre-diabetes,cardiometabolic risk and/or metabolic syndrome. Because of its uniquecentral mechanism of action, this therapy may be effectively combinedwith various peripheral acting agents that target specific peripheralbiochemistry operative in manifesting particular elements of metabolicdisease that may not be fully alleviated by dopamine agonist therapy,such as HMGCoA reductase inhibitors to reduce elevated plasmacholesterol, anti-hypertensives to reduce blood pressure by mechanismsdifferent from those of dopamine agonist therapy, and anti-diabetesagents that augment the resetting effect of dopamine agonists on glucosemetabolism such as postprandial insulin secretagouges or insulin itself,anti-inflammatory agents, and anti-coagulative agents.

There is a need in the art for improved formulations for administeringdopamine agonists, particularly for the treatment of metabolic diseases.Accordingly, the improved formulations suitable for administeringparenteral dopamine agonists disclosed herein avoid problems and improvemethods for effectively treating metabolic disease associated with priorart formulations. The formulations disclosed herein avoid problems suchas, e.g., first-pass metabolism and production of undesirable sideeffects and influences on efficacy due to ingestion of the drug.

SUMMARY OF THE INVENTION

The present invention is directed to formulations for administeringdopamine agonists, including formulations comprising one or moredopamine agonist and one or more peripheral acting agent, and methods ofusing such formulations to treat metabolic disorders.

In one embodiment, the invention provides a dosage form comprising anactive agent comprising one or more dopamine agonists and apharmaceutically acceptable excipient, said dosage form being suitablefor parenteral administration and exhibiting a pharmacokinetic profilewith a plasma T_(max) from about 1 to about 90 minutes afteradministration, a plasma drug concentration of at least 50% C_(max) fora duration of about 90 to about 360 minutes, and a decrease in plasmalevel that may approximate first order elimination kinetics.

In another embodiment, the invention provides a method for treating ametabolic disorder or at least one key element thereof, comprisingadministering to a subject in need thereof a therapeutically effectiveamount of a dosage form comprising an active agent comprising one ormore dopamine agonists and a pharmaceutically acceptable excipient, saiddosage form being suitable for parenteral administration and exhibitinga pharmacokinetic profile with a plasma T_(max) from about 1 to about 90minutes after administration, a plasma drug concentration of at least50% C_(max) for a duration of about 90 to about 360 minutes, and adecrease in plasma level that may approximate first order eliminationkinetics.

In another embodiment, the invention provides a method of reducingelevated plasma norepinephrine levels comprising administering to asubject in need thereof a therapeutically effective amount of a dosageform comprising an active agent comprising one or more dopamine agonistsand a pharmaceutically acceptable excipient, said dosage form beingsuitable for parenteral administration and exhibiting a pharmacokineticprofile with a plasma T_(max) from about 1 to about 90 minutes afteradministration, a plasma drug concentration of at least 50% C_(max) fora duration of about 90 to about 360 minutes, and a decrease in plasmalevel that may approximate first order elimination kinetics.

In another embodiment, the invention provides a method of reducingdiurnal plasma prolactin levels while maintaining an increase innocturnal plasma prolactin levels relative to diurnal plasma prolactinlevels comprising administering to a subject in need thereof atherapeutically effective amount of a dosage form comprising an activeagent comprising one or more dopamine agonists and a pharmaceuticallyacceptable excipient, said dosage form being suitable for parenteraladministration and exhibiting a pharmacokinetic profile with a plasmaT_(max) from about 1 to about 90 minutes after administration, a plasmadrug concentration of at least 50% C_(max) for a duration of about 90 toabout 360 minutes, and a decrease in plasma level that approximatesfirst order elimination kinetics.

In another embodiment, the invention provides a method for reducingelevated cardiovascular-related inflammatory factors or cardiovasculardisease or key elements of cardiovascular disease, comprisingadministering to a subject in need thereof a therapeutically effectiveamount of a dosage form comprising an active agent comprising one ormore dopamine agonists and a pharmaceutically acceptable excipient, saiddosage form being suitable for parenteral administration and exhibitinga pharmacokinetic profile with a plasma T_(max) from about 1 to about 90minutes after administration, a plasma drug concentration of at least50% C_(max) for a duration of about 90 to about 360 minutes, and adecrease in plasma level that may approximate first order eliminationkinetics.

In one embodiment, the invention provides a dosage form comprising anactive agent comprising one or more dopamine agonists and apharmaceutically acceptable excipient, said dosage form being suitablefor parenteral administration and exhibiting a pharmacokinetic profilewith a plasma T_(max) from about 5 to about 90 minutes afteradministration, a post C_(max) level of about one-half C_(max) withinabout 30 to about 150 minutes of T_(max), a post C_(max) level of aboutone-half C_(max) for a duration of about 90 to about 360 minutes, and adecrease in plasma level that may approximate first order eliminationkinetics.

In another embodiment, the invention provides a method for treating ametabolic disorder or key element thereof by administration of aparenteral dosage form containing one or more dopamine agonists whereinelevated plasma norepinephrine and prolactin levels are reduced and anocturnal plasma prolactin level is increased relative to the newlyestablished average diurnal circulating level of prolactin.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing a pharmacokinetic profile of a parenteraldosage formulation according to the present invention for administeringa dopamine agonist.

FIG. 2 is a graph showing another pharmacokinetic profile of aparenteral dosage formulation according to the present invention foradministering a dopamine agonist.

FIG. 3 is a graph showing the effect of 7 day parenteral treatment withthe 34 Gel formulation (10 mg/kg) on insulin resistance (HOMA-IR) in theSHR rat model.

FIG. 4 is a graph showing the effect of 7 day parenteral treatment withthe 34 Gel formulation (10 mg/kg) on plasma insulin levels in the SHRrat model.

FIG. 5 is a graph showing the effect of 7 day parenteral treatment withthe 34 Gel formulation (10 mg/kg) on blood pressure in the SHR ratmodel.

FIG. 6 is a graph showing the effect of 7 day parenteral treatment withthe 34 Gel formulation (10 mg/kg) on body weight change in the SHR ratmodel.

FIG. 7 is a graph showing the effect of 7 day parenteral treatment withthe 34 Gel formulation (10 mg/kg) on body weight in the SHR rat model.

FIG. 8 is a graph showing the effect of 7 day parenteral treatment withthe 34 Gel formulation (10 mg/kg) on endothelin-1 levels in the SHR ratmodel.

DETAILED DESCRIPTION OF THE INVENTION

Disclosed herein are parenteral dosage forms suitable for administering,e.g., one or more dopamine agonist alone or in combination with one ormore anti-hypertensive, anti-hypercholesterolemic,anti-hypertriglyceridemic, anti-inflammatory, anti-coagulative, oranti-hyperglycemic agent. The dosage forms exhibit physiologicalattributes, e.g., a pharmacokinetic profile that induces certainneuroendocrine effects and enables treatment of metabolic disordersand/or key elements thereof. The dosage forms comprise an active agentor active agents and one or more excipients.

The dosage forms are particularly suited for treatment of metabolicdisorders and/or key elements of these disorders including but notlimited to, type 2 diabetes, prediabetes (impaired fasting glucose orimpaired glucose tolerance), metabolic syndrome or indices (keyelements) thereof (increased waist circumference, increased fastingplasma glucose, increased fasting plasma triglycerides, decreasedfasting high density lipoprotein level, increased blood pressure),insulin resistance, hyperinsulinemia, cardiovascular disease (or keyelements thereof such as arteriosclerosis, coronary artery disease,peripheral vascular disease, or cerebrovascular disease), congestiveheart failure, obesity, elevated plasma norepinephrine, elevatedcardiovascular-related inflammatory factors, hyperlipoproteinemia,atherosclerosis, hyperphagia, hyperglycemia, hyperlipidemia, andhypertension or high blood pressure, increased plasma postprandialtriglyceride or free fatty acid levels, increased cellular oxidativestress or plasma indicators thereof, increased circulatinghypercoagulative state, renal disease including renal insufficiency.

The dosage forms comprising dopamine agonist(s) and a peripheraltargeting agent(s) could be applied to specific patient populations asneeded, for example, dopamine agonist+HMGCoA reductase formulations forhypercholesterolemic-type 2 diabetics or dopamineagonist+anti-hypertensive medication for very hypertensive-type 2diabetics, and other combinations. Moreover, this combination dopamineagonist+peripheral targeting agent therapy could be of further uniquevalue and utility if it were within a singular formulation that wouldallow for the appropriate dosing of each of the components. In effect,such a formulation(s) could be the “poly pill” the medical andpharmaceutical communities have been seeking to treat the multipleabnormalities associated with common metabolic diseases of type 2diabetes, obesity, metabolic syndrome and/or cardiometabolic risk with asingle-dosage, once-daily medicinal. Parenteral formulations would allowfor optimal, low dosing of the dopamine agonist(s) as described hereinas well as, in certain embodiments, for HMGCoA reductase inhibitors thatalso undergo first-pass hepatic metabolism.

The combination parenteral formulations according to this invention alsoprovide the ability to tailor metabolic disease therapy on a subject bysubject basis that includes a central acting “resetting” component thataddresses global metabolic disease (hypertension, dyslipidemia, andhyperglycemia) with any of several peripheral acting agents that addressspecific targets of metabolic disease (either hypertension,dyslipidemia, or hyperglycemia) as the need may be on an individualpatient basis. At the same time, the combination parenteral formulationsaccording to this invention also allow for the administration of smallerdoses of dopamine agonists and/or peripheral acting agents, and thus tomitigate or avoid altogether side-effects that may be associated withadministration of the dopamine agonists and the peripheral actingagents. For example, by having the peripheral anti-hypertensive agentreach peak concentrations a few hours after the dopamine agonist, thepotential for orthostatic hypotension as well as syncope, or loss ofconsciousness, is reduced or avoided. In another example, forcombinations with HMGCoA reductase inhibitors, lower dosages of both thedopamine agonist and HMGCoA reductase inhibitor can be used since bothare subject to first pass hepatic metabolism (and for ergot-relateddopamine agonists both actually utilize the same cytochrome P450-3Apathway for metabolism). If the HMGCoA reductase inhibitor is releasedafter the dopamine agonist then there is less chance of competitiveinteraction at the liver for metabolism, a beneficial circumstance asthis allows for better prediction of circulating dose for each compound.This will reduce the potential side effects on muscle pain that can beobserved with each of these agents. In a further example, forcombinations of dopamine agonists with insulin secretagogues (e.g.,continuous or, preferably, post-prandial insulin secretagogues), suchformulations allow for once-daily dosing—the formulations according tothis invention facilitate the immediate release of insulin, followed byanother release of insulin four hours later, thus facilitating insulinrelease at the proper times after breakfast and lunch, while at the sametime minimizing the risk of hypoglycemia, a serious consideration withall anti-diabetes medications.

The parenteral dosage forms disclosed herein have desirable propertiesrelative to oral dosage forms, including improved effectiveness of adelivered drug in treating metabolic disease and/or key elements ofmetabolic disease, administration of smaller amounts of dopamine agonistor dopamine agonists to achieve therapeutic effect, reduced circulatinglevels of active metabolites of the drug, increased ratio of circulatinglevel of drug to metabolites, improved therapeutic index (i.e., drugeffect/drug side effect), elimination of first-pass metabolism, andavoidance of gastrointestinal side effects due to drug interaction withdopamine agonist binding sites within the gut. Additionally, dosageforms disclosed herein have the advantage that they can beself-administered by patients without close medical supervision.

Use of the compositions described herein to treat metabolic diseaseaccomplishes improved results relative to an equivalent dosage of orallyadministered dopamine agonists. In one aspect, smaller dosages ofparental formulations can produce an effective dose equivalent to higherdosages of oral formulations of the same dopamine agonist(s). In anotheraspect, administration of smaller dosages of dopamine agonists resultsin reduced amounts of dopamine agonist(s) metabolites, particularly inthe case of ergot-related dopamine agonists. In still another aspect,administration of parenteral formulations results in reduced productionof metabolites thought to have biological activities that counteract theactivities of the parent compound as compared to administration of oralformulations having the same amount of active agent. The inventors ofthe present application have also surprisingly found that dopamineagonists used in the treatment of metabolic disease, when used at theappropriate dosages and at pre-determined times of day as describedherein are more effective when the active metabolite levels are reduced.Thus, parenteral dosage forms have a greater comparative therapeuticeffectiveness relative to equi-molar circulating concentrations of theoral dosage forms in part because of the reduced relative levels ofactive metabolites.

Accordingly, a parenteral dosage form of dopamine agonist(s) thatproduces an equivalent T_(max) level as that of an oral formulation ofdopamine agonist(s) can increase the relative dopamine agonistparent/metabolite ratio in the circulation and, thus, improve theeffectiveness of the dopamine agonist(s) in treating metabolic diseaserelative to an equivalent T_(max) level of orally administered dopamineagonist(s). For example, a therapeutically effective amount of dopamineagonist(s) administered via an oral dosage form for treatment ofmetabolic disease is 1 mg per day and will produce 100 μg of agonist(s)and 900 μg of metabolites (due to first-pass metabolism) in thecirculation. By contrast, a parenteral dosage form may achieve the same“effective” dose of dopamine agonist(s) in the circulation resultingfrom the administration of 120 μg of dopamine agonist(s) since there islittle or no first-pass metabolism of the drug and only about 20 μg ofmetabolites are produced over time. Accordingly, the ratio ofdrug/metabolite is 100/900 for the oral administration and 100/20 forthe parenteral formulation. Thus, the counteractive effects of themetabolites on the metabolic activity of the parent compound(s) arereduced, particularly when administered as described herein.

In another aspect, the dosage forms disclosed herein are stable,remaining suitable for administration over a prolonged period instorage. Irreversible agglomeration in the dosage forms disclosed hereinis eliminated or reduced, even in storage for some months.

Active dopamine agonist agents for inclusion in dosage forms disclosedherein include, for example and without limitation, non-ergot andergot-related derivatives. Active dopamine agonist agents include D₁dopamine receptor agonists and/or D₂ dopamine receptor agonists. Incertain embodiments a D₁ dopamine agonist is administered to a subjectin need of treatment. In other embodiments a D₂ dopamine agonist isadministered to a subject in need of treatment. In yet other embodimentsof the present invention, a D₁ dopamine agonist is administered inconjunction with a D₂ dopamine agonist to a subject in need oftreatment.

Active peripheral acting agents for inclusion in dosage forms disclosedherein include, without limitation, anti-hypertensive,anti-inflammatory, anti-coagulative, anti-hypercholesterolemic,anti-hypertriglyceridemic, and/or anti-hyperglycemic agents. In certainembodiments, an active peripheral acting agent is an HMGCoA reductaseinhibitor.

The dosage forms disclosed herein may comprise, consist essentially of,or contain D₁ dopamine receptor agonist, alone or in combination with aD₂ dopamine receptor agonist, and further optionally in combination withone or more active peripheral acting agent.

As used herein the terms “conjoined” treatment or administration ortreatment or administration “in conjunction” mean that a subjectreceives at least a first amount of a first active agent and a secondamount of a second active agent. Active agents may be administered in asingle formulation or dosage form or in separate dosage forms. Agentsadministered in separate dosage forms may be administered at the sametime or at different times. For example a D₁ agonist and D₂ agonist canbe administered at the same time (in the same dosage form or in two ormore divided dosage forms) or sequentially at different times and indifferent dosage forms.

Therapeutically effective amounts of D₁ agonist for humans andvertebrates when administered parenterally alone (not conjoined to a D₂agonist) are typically within the range of about 1.0 μg/kg/day to about10.0 mg/kg/day. Preferably, the therapeutically effective amounts of D₁agonist for humans and vertebrates when administered alone are typicallywithin the range of about 1.0 μg/kg/day to about 7.0 mg/kg/day. Morepreferably, the therapeutically effective amounts of D₁ agonist forhumans and vertebrates when administered alone are typically within therange of about 1.0 μg/kg/day to about 5.0 mg/kg/day. Most preferably,the therapeutically effective amounts of D₁ agonist for humans andvertebrates when administered alone are typically within the range ofabout 2.0 μg/kg/day to about 3.0 mg/kg/day.

Therapeutically effective amounts of D₂ agonist for humans andvertebrates when administered parenterally alone (not conjoined to a D₁agonist) are typically within the range of about 0.5 μg/kg/day to about300 μg/kg/day. Preferably, the therapeutically effective amounts of D₂agonist for humans and vertebrates when administered alone are typicallywithin the range of about 0.5 μg/kg/day to about 250 μg/kg/day. Morepreferably, the therapeutically effective amounts of D₂ agonist forhumans and vertebrates when administered alone are typically within therange of about 0.5 μg/kg/day to about 200 μg/kg/day. Most preferably,the therapeutically effective amounts of D₂ agonist for humans andvertebrates when administered alone are typically within the range ofabout 1.0 μg/kg/day to about 150 μg/kg/day.

Where therapeutically effective amounts of D₁ and D₂ agonist(s) forhumans and vertebrates are administered parenterally in conjunction,about 15% less of each of the D₁ and D₂ agonist(s) may be used.Preferably, where therapeutically effective amounts of D₁ and D₂agonist(s) for humans and vertebrates are administered parenterally inconjunction about 17% less of each of the D₁ and D₂ agonist(s) are used.More preferably, where therapeutically effective amounts of D₁ and D₂agonist(s) for humans and vertebrates are administered parenterally inconjunction about 20% less of each of the D₁ and D₂ agonist(s) are used.Most preferably where therapeutically effective amounts of D₁ and D₂agonist(s) for humans and vertebrates are administered parenterally inconjunction about at least 25% less of each of the D₁ and D₂ agonist(s)are used.

A dopamine agonist in a non-colloidal form is typically compounded to aparticle size (d₉₀) in the range of about 5 to 175 μm. Preferably, thedopamine agonist in the non-colloidal form is compounded to a particlesize in the range of about 5 to 150 μm. More preferably, the dopamineagonist in the non-colloidal form is typically compounded to a particlesize in the range of about 5 to 125 μm. Most preferably, the dopamineagonist in the non-colloidal form can be compounded to a particle sizeof about 10 to 100 μm.

A dopamine agonist in colloidal form is typically compounded to aparticle size in the range of about 0.1 to 5.0 μm. Preferably, thedopamine agonist in colloidal form is typically compounded to a particlesize in the range of about 0.1 to 3.0 μm. More preferably, the dopamineagonist in colloidal form is typically compounded to a particle size inthe range of about 0.1 to 2.0 μm. Most preferably, the dopamine agonistin colloidal form is typically compounded to a particle size in therange of about 0.1 to 1.0 μm.

A D₁ dopamine agonist activates or potentiates D₁ dopamine receptors orD₁-like receptors such as D₁ and D₅ dopamine receptors. The D₁ agonistis also a selective agonist for the D₁ receptor over the D₂ receptor(i.e., the compound has a lower K_(i) or EC₅₀ for the D₁ receptor thanthe D₂ receptor). In one embodiment, the D₁ agonist is a weak agonist(e.g., K_(i) or EC₅₀ of greater than 1 μM or 1 mM) or a partial agonist(binding affinity less than that of endogenous dopamine for D2 sites) oris not a D₂ agonist (e.g., K_(i) or EC₅₀ of greater than 10 mM).

D₁ dopamine agonists that are capable of activating or potentiating D₁dopamine receptors are well known in the art. Examples of D₁ agonistsinclude, without limitation, dopamine, apomorphine, SKF38393,dihydrexidine, SKF 75670, SKF 82957, SKF 81297, SKF 82958, SKF 82598,A77636, A68930, and SKF 82526 (fenoldopam), and racemictrans-10,11-dihydroxy 5,6,6a, 7,8,12b-hexahydro and related benzazepineanalogs, and those D₁ agonists disclosed in the references cited herein.A preferred D₁ dopamine agonist is SKF 38393 or apomorphine. See e.g.,U.S. Pat. No. 6,855,707, the contents of which are incorporated hereinby reference.

D₂ dopamine agonists activate or potentiate D₂ dopamine receptors (e.g.,D₂, D₂ short and D₂ long receptors, D₄, and D₄ dopamine receptors). Inone embodiment, the D₂ agonist is a selective agonist for the D₂receptor over the D₁ receptor. In a further embodiment, the D₂ agonistis a weak D₁ agonist or is not a D₁ agonist. Examples of D₂ dopamineagonists are well known in the art.

Ergot-related D₂ agonists include, for example and without limitation,2-bromo-α-ergocriptine (bromocriptine), terguride, dihydroergotoxine(hydergine), erfotoxine, 6-methyl8β-carbobenzyloxy-aminoethyl-10-α-ergoline, 8-acylaminoergoline,6-methyl-8-α-(N-acyl)amino-9-ergoline, lisuride,dihydro-alpha-ergocriptine, dihydro-alpha-ergotoxine,6-methyl-8-α-(N-phenyl-acety)amino-9-ergoline, ergocornine,9,10-dihydroergocomine, any D-2-halo-6-alkyl-8-substituted ergoline, andD-2-bromo-6-methyl-8-cyanomethylergoline. Of these bromocriptine orlisuride or ergot-related compounds with little or no serotonin 5HT2Breceptor agonist activity is most preferred.

Examples of non-ergot-related dopamine D2 agonists include, withoutlimitation, ropinirole, piribedil, apomorphine, quinelorane, andtalipexole.

Examples of peripheral acting agents are, without limitation, substancesthat exhibit and anti-hypertensive, anti-inflammatory,anti-hypercholesterolemic, anti-hypertriglyceridemic, and/oranti-hyperglycemic effect.

Anti-hyptertensive agents include, for example and without limitation,agents that are angiotensin converting enzyme (ACE) inhibitors,angiotensin II receptor blockers (ARBs), calcium channel blockers,β-blockers, α-blockers, and diuretics. Examples of anti-hypertensiveagents include, for example and without limitation, bumetanide,ethacrynic acid, furosemide, torsemide, chlortalidone, epitizide,hydrochlorothiazide, chlorothiazide, bendroflumethiazide, indapamide,metolazone, amiloride, triamterene, spironolactone, atenolol,metoprolol, nadolol, oxprenolol, pindolol, propranolol, timolol,doxazosin, phentolamine, indoramin, phenoxybenzamine, prazosin,terazosin, tolazoline, bucindolol, carvedilol, labetalol, clonidine,methyldopa, amlodipine, felodipine, isradipine, nifedipine, nimodipine,nitrendipine, diltiazem, verapamil, captopril, enalapril, fosinopril,lisinopril, perindopril, quinapril, ramipril, trandopril, benzapril,candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan,valsartan, spironolactone, sodium nitroprusside, guanabenz,guanethidine, and reserpine.

Anti-hypercholesterolemic agents include, for example and withoutlimitation, HMGCoA reductase inhibitors agents (statins) and agents thatblock cholesterol absorption. Examples of anti-hypercholesterolemicagents include, for example and without limitation, atorvastatin,cerivastatin, fluvastatin, lovastatin, mevastatin, pravastatin,pitavastatin, rosuvastatin, simvastatin, cholestyramine, sitosterol,ezetimibe, gemfibrozil, clofibrate, nicotinic acid, colestipol, andcolesevelam. Preferred statin agents are atorvastatin, cerivastatin,fluvastatin, lovastatin, mevastatin, pravastatin, pitavastatin,rosuvastatin, and simvastatin.

Anti-hypertriglyceridemic agents include, for example and withoutlimitation, fibrates. Examples of anti-hypertriglyceridemic agentsinclude, for example and without limitation, gembfibrozil, clofibrate,bezafibrate, and walnut oil.

Anti-hyperglycemic agents include, for example and without limitation,agents that are biguanides, insulin secretagouges, and insulinsensitizers. Examples of anti-hyperglycemic agents include, for exampleand without limitation, insulin, sulfonylurea-based medications,metformin, repaglinide, nateglinide, glucosidase inhibitors,thiazolidinediones, GLP-1 analogs, and DPP IV inhibitors.

Dosage forms can include a dopamine agonist or dopamine agonistsformulated to achieve either faster or slower release of the drug intothe blood stream. Dosage forms are solid or free-flowing.

The term “solid” as used herein refers to a substance that is solid orsemi-solid at room temperature. Hence, as used herein, a “solid”substance may become liquid at, e.g., body temperature.

In certain embodiments, dosage forms can be formulated to have abiphasic release of active component, e.g., a fast release (a/k/aimmediate release) phase and a slow release (a/k/a delayed release)phase. The faster and slower release of the active agent may beseparated physically, by dividing components having differentcompositions, wherein each composition is characterized by faster orslower dissolution. In another embodiment, fast and slow release phasesare accomplished in a single, combined dosage form which may comprise,e.g., an outer layer that is characterized by fast dissolution and aninner layer that is characterized by slower dissolution.

In other embodiments, a dosage form may comprise a dissolved dopamineagonist that is characterized by fast dissolution and a colloidalsuspension of dopamine agonist that is characterized by slowerdissolution. Inclusion of a dopamine agonist having a small particlesize of about 0.02 to about 5.0 μm in a colloidal suspension promotesrapid dissolution and absorption. However, the rapid dissolution andabsorption of the dopamine agonist having a small particle size of about0.02 to about 5.0 μm in a colloidal suspension is slower than a dopamineagonist already in solution. Preferably, small particle size dopamineagonist is about 0.1 to about 3.0 μm. More preferably, small particlesize dopamine agonist is about 0.1 to about 2.0 μm. Most preferably,small particle size dopamine agonist is about 0.1 to about 1.0 μm.

Inclusion of dopamine agonist having a larger particle size (d₉₀) ofgreater than about 5.0 μm promotes slower dissolution and absorption.Preferably, inclusion of dopamine agonist having a larger particle size(d₉₀) of greater than about 5-150 μm promotes slower dissolution andabsorption. More preferably, inclusion of dopamine agonist having alarger particle size (d₉₀) of greater than about 5-125 μm promotesslower dissolution and absorption. Most preferably, inclusion ofdopamine agonist having a larger particle size (d₉₀) of greater thanabout 10-100 μm promotes slower dissolution and absorption.

In certain embodiments, small and large sized dopamine agonist(s)particles are present in formulations at an approximate ratio of 50/50.More preferably, small and large sized dopamine agonist(s) particles arepresent in an approximate ratio of 60/40. Most preferably, small andlarge sized dopamine agonist(s) particles are present in an approximateratio of 70/30.

In certain embodiments, the small particle size component is 1.0 μmwithin a tablet or other solid dosage form and the large particle sizeis 1 to 100 μm.

A prolactin inhibitor (such as bromocriptine) can be administered to amammalian subject (particularly to a human) at a pre-determined timeduring a 24-hour period if that subject has abnormally high daytimeprolactin levels (at least 1 Standard Error of the Mean (SEM) higherthan any of the normal daytime levels for a subject of the same speciesand sex). The administration and its timing are designed to decrease thesubject's abnormally high daytime prolactin levels. However, a prolactinstimulator may need to be administered at a different pre-determinedtime during a 24-hour period, if the subject has abnormally lownight-time prolactin levels, to increase these night-time prolactinlevels to be preferably no lower than approximately the normalnight-time prolactin levels for the same sex. It is also possible thatboth a prolactin inhibitor and a prolactin stimulator may need to beadministered at different times to the same subject to bring about botha decrease in daytime prolactin levels and an increase in night-timeprolactin levels.

Dosage formulations may further comprise, without limitation, one ormore of the following: excipients, non-aqueous solvent, pharmaceuticallyacceptable suspending medium, carriers or diluents, surface activecompounds, regulators for adjusting the osmolality, bioadhesives,polymers, permeabilizing agents, stabilizers, anhydrous mucosal tissueirritant-reducing agents, fillers, binders, disintegrants, lubricants,flavoring agents and sweeteners, gelling agents, inert gas,antioxidants, preservatives, wetting agents, surfactants, releasecontrolling agents, dyes, binders, suspending agents and dispersingagents, colorants, film forming agents, plasticizers or any combinationof two or more of the foregoing.

Excipients used in dosage forms will vary according to the type ofparenteral dosage form. Suitable excipients for dosage forms are wellknown to those of skill in the art and will vary according to the activeagent, mode of administration, and desired release profile of activeagent. Non-limiting examples of the suitable excipients for use informulations are provided below.

The term “pharmaceutically acceptable excipient(s)” is intended todenote any material, which is inert in the sense that it substantiallydoes not have a therapeutic and/or prophylactic effect per se. Such anexcipient is added with the purpose of making it possible to obtain apharmaceutical composition having acceptable technical properties.

Examples of non-aqueous solvents include, without limitation, propyleneglycol, glycerol, short-chain substituted or non-substituted alcoholssuch as ethanol, isopropanol, or propanol. In a certain embodiment, thenon-aqueous solvents may include, without limitation, various glycolsand/or alcohols alone or in combination, so that therapeutic dosescontain non-toxic solvent volumes of, e.g., 0.02 to 0.5 ml.

Examples of pharmaceutically acceptable suspending mediums or matricesinclude, without limitation, synthetic, semisynthetic or natural oilswhich can preferably be employed are medium chain length triglycerideswith a chain length of from C₈ to C₁₀ in the carboxylic acid moiety,soybean oil, sesame oil, peanut oil, olive oil, coconut oil, castor oil,sunflower oil, safflower oil or the corresponding hydrogenated oils ormixtures of at least two of the aforementioned oils, bentonite,ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitanesters, microcrystalline cellulose or derivatives thereof, plant gums,polyetheleneglycols of various size, aluminum metahydroxide, agar-agarand tragacanth, gelatins, or mixtures of two or more of thesesubstances, and the like.

Examples of pharmaceutically acceptable dispersing and suspending agentsinclude, but are not limited to, synthetic and natural gums, such asvegetable gum, tragacanth, acacia, alginate, dextran, sodiumcarboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone andgelatin.

Examples of suitable pharmaceutically acceptable carriers or diluentsinclude, but are not limited to, ethanol, water, glycerol, propyleneglycol, glycerin, diethylene glycol monoethylether, vitamin A and Eoils, mineral oil, PPG2 myristyl propionate, magnesium carbonate,potassium phosphate, silicon dioxide, vegetable oils such as castor oiland derivatives thereof, plant gums, gelatin, animal oils, solketal,calcium carbonate, dibasic calcium phosphate, tribasic calciumphosphate, calcium sulfate, microcrystalline cellulose, powderedcellulose, dextrans, dextrin, dextrose, fructose, kaolin, lactose,mannitol, sorbitol, starch, pre-gelatinized starch, sucrose, sugar etc.

Examples of surface active compounds include, without limitation,polyalkylene glycols such as polyethylene glycols, polypropylene glycolsor ethylene oxide, propylene oxide block copolymers, phospholipids,ethers or esters of saturated or unsaturated fatty alcohols or fattyacids with polyalkylene glycols such as polyethylene glycols orpolypropylene glycols, polysorbates such as mono-, di- or triesters ofsaturated or unsaturated fatty acids, particularly preferably oleicacid, lauric acid, palmitic acid or stearic acid, and sorbitol and/orits anhydride, each of which may have up to 20 mol of ethylene oxideunits per mole of sorbitol or anhydride, preferably polyethoxysorbitanmonolaurate with 20 ethylene oxide units, polyethoxysorbitan monolauratewith 4 ethylene oxide units, polyethoxysorbitan monopalmitate with 20ethylene oxide units, polyethoxysorbitan monostearate with 20 ethyleneoxide units, polyethoxysorbitan monostearate with 4 ethylene oxideunits, polyethoxysorbitan tristearate with 20 ethylene oxide units,polyethoxysorbitan monooleate with 20 ethylene oxide units,polyethoxysorbitan monooleate with 5 ethylene oxide units orpolyethoxysorbitan trioleate with 20 ethylene oxide units, or a mixtureof at least two of the aforementioned surface-active compounds.

Examples of regulators for adjusting the osmolality include, withoutlimitation, water-soluble, physiologically tolerated compounds such asinorganic salts, e.g., alkali metal salts, preferably sodium chloride,sugars, e.g. sucrose or dextrose, sugar alcohols, e.g., mannitol, orpolyalkylene glycols, e.g., polyethylene glycols, preferably having amolecular weight of from 1,000 to 8,000 g/mol. It is also possible touse a mixture of at least two representatives of different classes ofregulators or at least two representatives of one class of regulatorsfor adjusting the osmolality.

Bioadhesives are included, for example, in adhesive tablets, solutions,colloidal suspensions, gels, ointments, patches, films, pastes, andlozenges. Examples of bioadhesives polymers include, without limitation,Benecel® MP814, Kollidon, chitosan, cellulose derivatives, Carbopol934P, Carbopol 974P, 1Voveou AA-1, carbopole resins, carbomer, xanthangum, polycarbophil and polyethylene oxide combined with an inert diluentand an active ingredient, and ionic polysaccharides. Several syntheticand semi-synthetic bioadhesive polymers of different molecular weightand variations in degree of substitution include, without limitation,hydroxyethylcellulose, polyvinylalcohol, polyacrylic acid, sodiumcarboxymethylcellulose, polyvinylpyrrolidone, polyethylene glycols andothers. Mucosal adhesion of these bioadhesive formulations is based onthe interpenetration of hydrated hydrocolloid chains of the bioadhesiveformulation and glycoprotein chains of the oral mucosa.

Examples of suitable film forming agents include, but are not limitedto, hydroxypropylmethylcellulose, ethylcellulose and polymethacrylates.

Examples of suitable plasticizers include, but are not limited to,polyethylene glycols of different molecular weights (e.g., 200-8000 Da),plant gums, and propylene glycol and triethyl citrate.

Examples of permeabilizing agents comprise, without limitation, bilesalts, fatty acids, fatty acid derivatives, fatty acid esters, such aslaureate, myristate and stearate monoesters of polyethylene glycol,enamine derivatives and alpha-keto aldehydes; sodium cholate; sodiumglycocholate; sodium deoxycholate; sodium lauryl sulfate; sodiumsalicylate; sodium ethylenediaminetetraacetic acid (EDTA); aprotinin;azone; sodium 5-methoxysalicylate; 1-oleylazacycloheptan-2-one; and/orsilicas with a high affinity for aqueous solvents, such as theprecipitated silica better known by the trade mark Syloid®,maltodextrins, β-cyclodextrins, surfactants, chelators, cyclodextrins,chitosan, and lower alcohols.

Examples of stabilizers include, without limitation, citric acid,ascorbic acid, oleic acid, caprylic acid, capric acid,polyvinylpyrrolidone, waxes, block co-polymers, poloxamers, Poloxamer188 and 407, poloxamines, Poloxamine 908, polyvinyl pyrrolidone,polyvinyl alcohol, gelatine, polysaccharide, hyaluronic acid, chitosan,derivatives of chitosan, polyacryl acid, derivatives of polyacryl acid,polycarbophil, cellulose derivatives, methyl cellulose, hydroxypropylcellulose, carboxymethyl cellulose, sugar esters, saccharosemonostearate, sodium citrate individually, fatty acids, fatty alcohols,alcohols, long chain fatty acid esters, long chain ethers, hydrophilicderivatives of fatty acids, polyvinylethers, polyvinyl alcohols,hydrocarbons, hydrophobic polymers, moisture-absorbing polymers, andcombinations thereof.

Examples of anhydrous mucosal tissue irritant-reducing agent include,without limitation, plant oils like but not limited to olive oil, cornoil or mineral oil.

Examples of fillers include, without limitation, microcellulose, e.g.,ProSolv; Pharmaburst; Cab-o-sil; and saccharides, e.g., mannitol,lactose, xylitol and mixtures thereof.

Examples of suitable binders include, without limitation, eitherindividually or in combination, such binding agents as sucrose, gelatin,glucose, starch, cellulose materials, polyethylene glycols, povidone,methylcellulose, sodium carboxymethylcellulose, sodium alginate, agar,alginic acid and salts of alginic acid, calcium carrageenan, magnesiumaluminum silicate, polyethylene glycol, guar gum, polysaccharide acids,bentonites, polyvinylpyrrolidone (povidone), hydroxymethyl polyvinylpyrolidone, polymethacrylates (such as Eudragit), methylcellulose,hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (Klucel™),ethyl cellulose (Ethocel™), hydroxypropylmethylcellulose, pregelatinizedstarch (such as National™ 1511 and Starch 1500), sucrose, lactose,starch paste, povidone polyethylene glycol, Pullulan and corn syrup,waxes, and natural and synthetic gums, such as acacia, tragacanth,vegetable gum, castor oil, microcrystalline cellulose, dextrin, liquidglucose, guar gum, pectin, PEG, povidone, pregelatinized starch etc.

Examples of suitable disintegrants include, without limitation, starchessuch as maize starch and rice starch, cross-linked N-vinyl-2-pyrrolidone(CLPVP), alginic acid or alginates, microcrystalline cellulose,hydroxypropyl cellulose and other cellulose derivatives, croscarmellosesodium, crospovidone, polacrillin potassium, starch, pregelatinizedstarch, Pharmablast® carboxymethyl starch (e.g. Primogel® and Explotab®(sodium starch glycolate and sodium carboxymethyl starch)), sodiumstarch glycolate, and formaldehyde casein. Effervescent disintegrantsinclude without limitation, for example, starch, potassium bicarbonate,and sodium bicarbonate in combination with citric or tartaric acids. Thedisintegrant is present as an intra-granular disintegrant orextra-granular disintegrant.

Examples of suitable lubricants include, without limitation, sodiumoleate, sodium stearate, sodium stearyl fumarate, stearic acid,magnesium stearate, sodium benzoate, sodium acetate, sodium chloride,calcium stearate or other metallic stearate, talc, waxes and glycerides,light mineral oil, PEG, glyceryl behenate, colloidal silica,hydrogenated vegetable oils, corn starch, sodium stearyl fumarate,polyethylene glycols, alkyl sulfates, sodium benzoate, and sodiumacetate.

Examples of suitable flavoring agents include, without limitation,menthol, peppermint, vanilla, fruit flavorings, and sweeteners, e.g.,aspartame or sodium saccharinate.

Examples of gelling agents include, without limitation,polyvinylpyrrolidone, hydroxypropylmethyl cellulose, plant gums, and thelike.

Examples of suitable inert gases include, without limitation, nitrogen,helium, etc.

Examples of additional additives include, but are not limited to,sorbitol, talc, and stearic acid.

Examples of suitable antioxidants include, but are not limited to citricacid, ascorbic acid, ascobyl palmitate, butylated hydroxyanisole,butylated hydroxytoluene (BHT), monothioglycerol, potassiummetabisulfite, propylgallate, tocoferol excipients.

Examples of suitable wetting agents include, but are not limited topolysorbate, sodium lauryl sulfate, sorbitan monolaurate, sorbitanmonooleate, sorbitan monopalmitate, sorbitan monostearate.

Examples of suitable release controlling agents include, but are notlimited to hydroxypropylmethylcellulose, hydroxypropylcellulose,ethylcellulose, hydroxyethylcellulose.

Examples of surfactants include, without limitation, anionic andnon-ionic surfactants such as sodium lauryl sulfate, poloxamers(copolymers of polyoxyethylene and polyoxypropylene), natural orsynthetic lecitins as well as esters of sorbitan and fatty acids, suchas Span® (Commercially available from Sigma-Aldrich Co., St. Louis,Mo.), esters of polyoxyethylenesorbitan and fatty acids, such asPolysorbates or Polysorbate® (Commercially available from SpectrumChemical, Gardena Calif.), polyoxyethylene stearates, such as Myrj®(Commercially available from Uniqema, New Castle, Del.), polyethoxylatedfatty acids such as, e.g., fatty acid mono- or diesters of polyethyleneglycol or mixtures thereof such as, e.g., mono- or diesters ofpolyethylene glycol with lauric acid, oleic acid, stearic acid, myristicacid, ricinoleic acid, and the polyethylene glycol is selected from PEG4, PEG 5, PEG 6, PEG 7, PEG 8, PEG 9, PEG 10, PEG 12, PEG 15, PEG 20,PEG 25, PEG 30, PEG 32, PEG 40, PEG 45, PEG 50, PEG 55, PEG 100, PEG200, PEG 400, PEG 600, PEG 800, PEG 1000, PEG 2000, PEG 3000, PEG 4000,PEG 5000, PEG 6000, PEG 7000, PEG 8000, PEG 9000, PEG 1000, PEG 10,000,PEG 15,000, PEG 20,000, PEG 35,000, polyethylene glycol glycerol fattyacid esters, i.e. esters like the above-mentioned but in the form ofglyceryl esters of the individual fatty acids; glycerol, propyleneglycol, ethylene glycol, PEG or sorbitol esters with e.g., vegetableoils like e.g., hydrogenated castor oil, almond oil, palm kernel oil,castor oil, apricot kernel oil, olive oil, peanut oil, hydrogenated palmkernel oil and the like, polyglycerized fatty acids like e.g.,polyglycerol stearate, polyglycerol oleate, polyglycerol ricinoleate,polyglycerol linoleate, propylene glycol fatty acid esters such as,e.g., propylene glycol monolaurate, propylene glycol ricinoleate and thelike, mono- and diglycerides like e.g. glyceryl monooleate, glyceryldioleate, glyceryl mono- and/or dioleate, glyceryl caprylate, glycerylcaprate etc.; sterol and sterol derivatives; polyethylene glycolsorbitan fatty acid esters (PEG-sorbitan fatty acid esters) such asesters of PEG with the various molecular weights indicated above, andthe various Tween(R) series (from ICI America, Inc.); polyethyleneglycol alkyl ethers such as, e.g., PEG oleyl ether and PEG lauryl ether;sugar esters like, e.g., sucrose monopalmitate and sucrose monolaurate;polyethylene glycol alkyl phenols like, e.g., the Triton(R) X or Nseries (Union Carbide Chemicals & Plastics Technology Corporation);polyoxyethylene-polyoxypropylene block copolymers such as, e.g., thePluronic(R) series from BASF Aktiengesellschaft, the Synperonic(R)series from ICI America, Inc., Emkalyx, Lutrol(R) from BASFAktiengesellschaft, Supronic etc.

The amount of compound(s) acting as surfactant is adjusted when employedfor such purpose, so as to moderate the solubility, permeability, andbioavailability of dopamine agonist(s). Preferably the ratio ofsurfactant to dopamine agonist(s) on a mass basis is from about 0.001:1to about 1:1, more preferably from about 0.005:1 to 0.6:1 and mostpreferably from about 0.01:1 to about 0.25:1.

Examples of suitable lubricants and/or glidants include, withoutlimitation, either individually or in combination, such lubricantsand/or glidants as glyceryl behenate (Compritol™ 888); metallicstearates (e.g., calcium, sodium stearates, or other long chain fattyacid salts); stearic acid; hydrogenated vegetable oils (e.g.,Sterotex™); talc; waxes; Stearowet™; boric acid; sodium benzoate andsodium acetate; sodium chloride; DL-Leucine; polyethylene glycols (e.g.,Carbowax™ 4000 and Carbowax™ 6000); sodium oleate; sodium benzoate;sodium acetate; sodium lauryl sulfate; sodium stearyl fumarate (Pruv™);and magnesium lauryl sulfate.

Additional examples of suitable anti-adherents or glidants include,without limitation, either individually or in combination, suchanti-adherents as talc, cornstarch, DL-Leucine, sodium lauryl sulfate,and metallic stearates.

Suitable examples of preservatives include, without limitation, citricacid, vitamin C, vitamin E, 1,1,1-trichloro-2-methyl-2-propanol,phenylethyl alcohol, sorbic acid, benzyl alcohol,alkylbenzyldimethylammonium chloride with a chain length of from C₈ toC₁₈ in the alkyl moiety, m-cresol or alkyl-4-hydroxybenzoate.

The term “parenteral dosage form” is defined herein to mean a drugdosage form that provides for the absorption of a substantial amount ofthe drug through other than the gastric and/or intestinal mucosa of theGI tract.

Routes of parenteral administration include, without limitation, buccal,sublingual, subcutaneous, nasal, oral, otic, ocular, rectal, vaginal, orupper respiratory mucosa, or through the skin or lungs. Accordingly, thedosage forms include, without limitation, injection, oral, otic,ophthalmic, or nasal sprays or drops, sublingual and/or buccal sprays,drops, tablets, solutions, colloidal suspensions, and/or ointments, hardcapsule and soft capsules, tablets, coated tablets, or sachets, lozenge,films, chewing gum, chewable tablet, liquid gargle, skin patch,ointment, lotion, or cream, a respiratory inhaler, aerosols, or rectalor vaginal suppository.

Dosage forms may be administered by injection. Injection can be, forexample, subcutaneous, intradermal, and/or intraperitoneal.

The pH of the solution or solvent-based dosage forms of the inventionshould preferably be in the range from pH 3 to pH 9 in order to avoidfurther risks of cell and tissue damage.

The following dosage forms are provided as non-limiting examples. Dosageforms for nasal administration include nasal sprays and/or drops and/orapplication of nasal ointments. Dosage forms for sublingual or buccaladministration include oral spays, drops, solutions, colloidalsuspensions, tablets, ointments, lozenges, films, chewing gums, chewabletablets, and/or liquid gargle. Dosage forms for auricular or ocularadministration include sprays, drops, ointments, lotions and/or creams.Dosage forms for rectal administration include suppository, spray,drops, ointment, lotion and/or cream. Dosage forms for vaginaladministration include suppository, spray, drops, ointment, lotionand/or cream. Dosage forms for upper respiratory mucosa or pulmonaryadministration include a respiratory inhaler, e.g., nebulizer. Dosageforms for transdermal administration include skin patches, dermal spray,drops, ointment, lotion and/or cream.

Solid parenteral dosage forms preferably include a dopamine agonist(preferably an ergot alcohol derivative most preferably bromocriptine),an non-acrylic type of mucoadhesive (e.g., PVP, Benecel® and notCarbopol®), and citric acid to enhance stability and accelerate releaseof dopamine agonist. In the absence of citric acid, API was unstable inthe acrylic based solutions (50% of the drug decomposed after 90minutes). Citric acid enhanced the stability of the dopamine agonistpreparations.

Preferred routes of administration are, subcutaneous injection, buccal,sublingual, nasal and transdermal. More preferred routes ofadministration are buccal, sublingual and nasal. Particularly preferreddosage forms include subcutaneous injections, sublingual or buccaldosage forms, and skin patches.

Where the dosage form is to be injected or administered via a liquidcarrier (as for example in sublingual administrations) it may beadministered using two different vehicles for the two differentsolutions in one syringe. Such a syringe may have two vessels and ports,each specific to the two solutions. Alternatively, the two differentsolutions could be combined into one vessel.

Where parenteral administration is subcutaneous, suitable forms forinjection may include a hydrophobic or hydrophilic suspension medium.

One embodiment of the formulations disclosed herein therefore comprisessuspending the salt of the active ingredient or active ingredients in ahydrophobic pharmaceutically acceptable suspending medium. Thishydrophobic suspending medium may preferably be based onpharmaceutically acceptable synthetic, semisynthetic or natural oils ormixtures of at least two of these oils.

The suspending medium is provided preferably in amounts of from 10 to90% by weight based on the suspending medium.

It is also possible to employ dosage forms via a physiologicallytolerated hydrophilic suspending medium and wherein the activeingredient is a salt being a D₁ agonist and/or a non-ergot-related D₂agonist. The hydrophilic suspending medium is preferably based on water.

Besides one or more regulators to adjust the osmolality, the dosageforms may further comprise one or more representatives the otheraforementioned excipients.

In order to minimize or completely eliminate the risk of cell and tissuedamage, the osmolality, i.e., the tonicity of the aqueous dosage forms(if so employed) of the invention which are to be administeredparenterally, is preferably adjusted so that they are isotonic or atleast approximately isotonic to the physiological osmolality. Theosmolality of the dosage forms of the invention which can beadministered parenterally is therefore preferably adjusted so that it isin the range from 250 to 400 mOsm/kg, particularly preferably in therange from 260 to 320 mOsm/kg and very particularly preferably in therange from 280 to 300 mOsm/kg.

It is also possible where appropriate to employ a regulator to adjustdifferent properties of the dosage forms. For example, a surface-activecompound can also be used to adjust the osmolality of the administrationenvironment (e.g., sublingual or buccal area).

Dosage forms may further comprise one or more physiologically toleratedsurface-active compounds.

Parenteral dosage forms are typically administered in volumes from about0.01 to 0.75 ml. Preferably, the volume to be administered parenterallyis from about 0.01 to about 0.5 ml, more preferably from about 0.01 toabout 0.3 ml, and most preferably from about 0.01 to about 0.2 ml.

Where the dosage form is to be taken orally, the dosage form ispreferably suitable for buccal or sublingual administration of the drugvia the mucosa of the oral cavity. More preferably, the dosage form isof the sublingual type suitable for administration of the drug via themucosa of the oral cavity.

Typically, the buccal dosage form is placed in the buccal cavity betweenthe gum and the cheek, where it dissolves in the subject's saliva,releasing the medicament into the buccal cavity in close proximity tothe capillary bed of the oral mucosa. The sublingual dosage form isplaced beneath the tongue where it dissolves in the saliva to releasethe drug in close proximity to the capillary bed of the oral mucosa fortransmucosal absorption.

The pharmaceutically active agent in these oral dosage forms enters theblood in the capillary bed by diffusion through the mucosal tissue andis distributed in the bloodstream to the rest of the body. The rate atwhich the active agent is supplied to the body depends upon, among otherthings, the rate at which the dosage form dissolves in the mouth. Thephysical properties of the dosage form determine the degree of contactwith the mucosal tissues and consequently the efficiency of theabsorption of the medicament.

Where parenteral administration is accomplished via oral administration,absorption through the gastric and/or intestinal mucosa can besubstantially prevented by the use of certain components in theformulation such as bioadhesives, permeabilizing agents and stabilizersthat prevent and/or reduce the introduction of dopamine agonists intothe gastric and/or intestinal mucosa of the GI tract.

In certain embodiments, orally administered (sublingual or buccal)parental dosage forms comprise both rapid and slow soluble componentswhen introduced into the oral cavity as a function of the two distinctformulations within the single dosage form or dosage applicator.

Solid oral dosage forms (comprising fast and slow absorption components)may be characterized by their dissolution times in vitro. Solid oraldosage forms (comprising fast and slow absorption components) typicallyexhibit a dissolution time of about ten seconds to about 100 minutes.Preferably, oral dosage forms exhibit a dissolution time of about tenseconds to about 50 minutes. More preferably, oral dosage forms exhibita dissolution time of about 10 seconds to about 30 minutes. Mostpreferably, oral dosage forms exhibit a fast dissolution time of about10 seconds to about 20 minutes.

In certain embodiments, an oral dosage form is a film, e.g. a buccalfilm. The mechanical, bioadhesive, and swelling properties of films arecontrolled to be suitable for buccal administration. Films for buccaladministration are preferably flexible, elastic, soft yet sufficientlystrong to withstand breakage due to stress from handling such asunwrapping and mouth action and also exhibit good bioadhesiveness so asto be retained in the mouth for a desired duration. Swelling of films ispreferably avoided or limited, to prevent discomfort.

In certain embodiments, an oral dosage form is a sublingual dosage form.

Pharmacokinetic profiles of formulations are controlled by excipients.In certain embodiments a solid dosage formulation consists of at leastone dopamine agonist (for both fast and slower absorption), a filler(preferably mannitol, lactose, xylitol and mixtures thereof) or solventmatrix, a binder (e.g., Kollidon) to one or both of two sized dopamineagonist particles, and a disintegrant.

A binder is preferably employed in a minimum quantity to preventunnecessary reduction in the rate of dissolution for each of the “fast”and “slow” dissolution aspect of the dosage form. Preferred binders aresoluble in water. Preferred binders are polyvinyl pyrolidone,hydroxymethyl polyvinyl pyrolidone, and gelatin may also be used.

The proportion of the disintegrant may be 0.1 to 75% of the granule,preferably 1 to 60%, more preferably 1 to 40%.

A minimal proportion of lubricant is preferred, for example up to 1%,preferably about 0.8%. Use of an extra-granular lubricant alone ispreferred in order to minimize the hydrophobic properties of the dosageform.

Tablet may include conventional excipients typically present in anamount of about 10% of the total weight. These may include flavoringagents. Flavoring agents when used are typically present up to about 0.5to 5% by weight of the whole tablet. Sweeteners and further excipientsmay also include coloring agents, preservatives and fillers.

Preferred fillers are selected from saccharides. Mannitol, lactose,xylitol and mixtures thereof are preferred on account of theirsolubility and despite the water content of lactose in particular.Mannitol is preferably present in an amount of 20 to 40% w/w, and morepreferably present in an amount of 20 to 30% w/w. Lactose is preferablypresent in an amount of 30 to 60% w/w. Preferred fillers are anhydrous.

In certain transmucosal embodiments, a first active agent of particularparticle size is complexed with or administered together with a secondagent, e.g., an agent that facilitates penetration of the active agentinto a tissue, into cells, or into the blood stream. In one embodiment,an active agent is provided together with a permeation enhancer.

Exemplary agents enhancing uptake of a active agent(s) into cellsinclude fatty acids, derivatives of fatty acids, lipids or complexes oflipids or comprising lipids, e.g., liposomes. Liposomes are hollowspherical vesicles composed of lipids arranged in a similar fashion asthose lipids which make up the cell membrane. They may have an internalaqueous space for entrapping water soluble compounds and range in sizefrom 0.05 to several microns in diameter. For example, a liposomedelivery vehicle originally designed as a research tool, Lipofectin, hasbeen shown to deliver intact molecules to cells. Liposomes offer severaladvantages: they are non-toxic and biodegradable in composition; theydisplay long circulation half-lives; and recognition molecules can bereadily attached to their surface for targeting to tissues. Lipidaggregates can be formed with macromolecules using, e.g., cationiclipids alone or including other lipids and amphiphiles such asphosphatidylethanolamine. Liposomes comprising cationic lipids arefavored for delivery of negatively charged molecules.

Other drug delivery vehicles that can be used include hydrogels,cyclodextrins, biodegradable polymers (surgical implants ornanocapsules), and bioadhesive microspheres.

Agents may also be provided together with a sustained release mechanism,which may include, e.g., polymer microspheres, and other mechanismsknown to those skilled in the art to vary the rate of release of anagent. Accordingly, an active agent may be provided together with atleast one permeation or permeability enhancer, and/or optionally, maycomprise at least one sustained release mechanism and/or at least onebioadhesive. Examples of permeation enhancers include, but not limitedto, fatty acids, Cavitron, thiomers, menthol, and polyoxyethylene.

Where the dosage form is a transdermal patch, dopamine agonist may bemicronized or solvated and added to a dermal delivery system such ascommonly used in pharmaceutical “patches” for sustained drug deliveryover long periods (hours) of time.

In one embodiment, a gel composition comprising one or more dopamineagonist is applied to the skin of a person having a metabolic disease orexhibiting key elements associated therewith. Oral compositions can beapplied in measured quantity as a lotion or ointment. Such compositionsmay be applied, e.g., to a backing layer to make a dosage form whichprovides a suitable adhesive means to adhere the dosage form to thesubject to be treated. For example, the backing layer can be shapedaround the sides of the applied gelled dopamine agonist composition andthen extended horizontally. To the underside of the thus formedperipheral ring can be applied a suitable adhesive layer for adheringthe dosage unit to the skin of the subject to be treated.

Skin patches may be single-layer drug in adhesive, multi-layer drug inadhesive, reservoir or matrix type patches. The single-layer drug inadhesive patch comprises an adhesive layer that also contains one ormore dopamine agonist. In this type of patch the adhesive layer not onlyserves to adhere the various layers together, along with the entiresystem to the skin, but is also responsible for the releasing mechanismof the dopamine agonist(s). The adhesive layer is surrounded by atemporary liner and a backing. The multi-layer drug in adhesive patch issimilar to the single-layer system in that both adhesive layers are alsoresponsible for the releasing mechanism of the dopamine agonist(s). Themulti-layer system is different however in that it adds another layer ofdrug-in-adhesive, usually separated by a membrane (but not in allcases). This patch may also have a temporary liner-layer and a permanentbacking. The reservoir patch is unlike the single-layer and multi-layersystems in that the reservoir transdermal system has a separate druglayer comprising dopamine agonist(s) for two different delivery rates tothe skin. The drug layer is a liquid compartment containing a drugsolution or suspension separated by the adhesive layer. This patch mayhave a backing layer. The matrix patch has a drug layer of a semisolidmatrix containing a dopamine agonist(s) solution or suspension. Theadhesive layer in this patch surrounds the drug layer and may partiallyoverlay it.

Transdermal patches may comprise a gelling agent, preferably saturatedor highly saturated with the selected dopamine agonist or dopamineagonists. The gelling agent selected is biocompatible, compatible withthe dopamine agonists, and permits the dopamine agonist to betransdermally absorbed.

Also, instead of gelling agent or in addition to a gelling agent, thehomogeneous mixture including dopamine agonist can be added to anabsorbent which is capable of absorbing the dopamine agonist. A suitableabsorbent can be selected from an absorbent cotton, a biocompatible andsuitable synthetic fibrous material including spun-bonded materials andother absorbents suggested to those skilled in the art. The finaldopamine agonist composition after addition of the gelling agent orabsorbent will have a suitable viscosity for use in transdermal therapy.

Where the dosage form is an aerosol formulation, it may be administeredusing two different vehicles for the two different solutions in onecontainer. Such a container may have two vessels and ports each specificto the two solutions. Alternatively, the two different solutions couldbe combined into one container.

The term “metabolic disorder” includes disorders associated withaberrant whole-body glucose, lipid and/or protein metabolism of aspecies and pathological consequences arising there from. Thesemetabolic disorders may or may not be associated with aberrant patternsin the daily levels (and fluctuations) of prolactin secretion.

The “key elements” of these metabolic disorders include but are notlimited to, type 2 diabetes, prediabetes (impaired fasting glucose orimpaired glucose tolerance), metabolic syndrome or indices (keyelements) thereof (increased waist circumference, increased fastingplasma glucose, increased fasting plasma triglycerides, decreasedfasting high density lipoprotein level, increased blood pressure),insulin resistance, hyperinsulinemia, cardiovascular disease (or keyelements thereof such as arteriosclerosis, coronary artery disease,peripheral vascular disease, or cerebrovascular disease), congestiveheart failure, obesity, elevated plasma norepinephrine, elevatedcardiovascular-related inflammatory factors, elevated plasma factorspotentiating vascular endothelial dysfunction, hyperlipoproteinemia,arteriosclerosis or atherosclerosis, hyperphagia, hyperglycemia,hyperlipidemia, and hypertension or high blood pressure, increasedplasma postprandial triglyceride or free fatty acid levels, increasedcellular oxidative stress or plasma indicators thereof, increasedcirculating hypercoagulative state, renal disease including renalfailure and renal insufficiency.

The phrase “dissolution profile” as used herein, refers to thedissolution of an agent over time. The dissolution can be measured asthe relative amount of agent dissolved over time, the amount of agentdissolved, or the concentration of the dissolved agent at a given time.The preferred method of determining dissolution rate is USP basketmethod at 100 RPM in 900 ml aqueous buffer 0.01N HCl, at 37° C.Alternative methods are equally acceptable including the USP paddlemethod and other suitable methods known to those of skill in the art.

As used herein, the term “pharmaceutically acceptable” refers to abiologically or pharmacologically compatible drug component for in vivouse, and preferably means a drug component approved by a regulatoryagency of the Federal or a state government or listed in the U.S.Pharmacopoeia or other generally recognized pharmacopoeia for use inanimals, and more particularly in humans.

The term “bioavailability” refers to the rate and extent to which adopamine agonist is absorbed into a biological system from anadministered drug product and becomes available at the site ofbiological action.

As used herein, a “therapeutically effective amount” refers to theamount of an active agent sufficient to treat metabolic disease and/orthe key elements of metabolic disease.

Pharmacokinetic Profile & Prolactin

Healthy (normal) subjects, i.e., lean members of a species not sufferingfrom such metabolic disease and/or key elements thereof have highlypredictable daily prolactin release profiles. In humans these releaseprofiles are characterized by a low and relatively constant prolactinlevel during the waking hours (day) followed by a sharp rise to a peakduring sleep (night) and subsequent more gradual tapering down to thewaking hours level by morning. One or more dopamine agonist can beadministered to a subject in need thereof to modify aberrant dailyprolactin level rhythms so that they resemble, or more closelyapproximate in phase and amplitude, the normal diurnal plasma prolactinlevel rhythms of lean, young and healthy members of the same species andsex. See e.g., U.S. Pat. Nos. 5,468,755; 5,496,803; 5,344,832,5,585,347, 5,830,895, and 6,855,707 and PCT applications US93/12701 andUS95/09061 (the disclosure of which is incorporated herein byreference). Such modulation of prolactin rhythms has been used to treattype 2 diabetes, obesity, insulin resistance, and hyperinsulinemia orhyperglycemia, hyperlipoproteinemia, hyperphagia, obesity, insulinresistance (impaired glucose tolerance), hyperlipidemia, etc.

The parenteral dosage forms of the present invention can produce aparticular pharmacokinetic profile of dopamine agonist that is effectivein sculpting the patients plasma prolactin profiles by reducingaberrantly elevated diurnal plasma prolactin levels to within low normaldaytime levels without extending an equivalent resulting plasmaprolactin level into the night-time (or sleep time hours) and thus doesnot result in equivalent daytime and night-time plasma prolactin levels,thus potentiating treatment of metabolic disorders and/or key elementsof metabolic disorders in subjects with such prolactin secretorydisorders. It must be appreciated however that “normalization” of theprolactin circadian rhythm is not necessarily a prerequisite for thedopamine agonist induced improvement in metabolism, in and of itself,but rather such “normalization” activity can function to potentiatedopamine agonist induced improvements in metabolic disease and keyelements thereof.

The parenteral dosage forms of the present invention can also produce aparticular pharmacokinetic profile that is effective in reducing levelsof elevated plasma norepinephrine concentration without the dopamineagonist having to be present in the circulation throughout the day. Suchinfluences of the parenteral dosage forms, while not a prerequisite fortheir activity on metabolic disease, potentiate improvements inmetabolic disease and key elements thereof.

Formulations desirably have a pharmacokinetic profile that enhancesefficacy of an active agent.

Pharmacokinetic profiles are indicative of the absorption anddisposition of active agent(s) and may be defined by plasmaconcentration data used to assess key pharmacokinetic parameters suchas, for example, T_(max), C_(max), AUC, and t_(lag). T_(max) is the timeto peak concentration. C_(max) is the peak concentration. AUC is thearea under the curve (AUC). t_(lag) is the absorption lag time.

The process of absorption can be seen as increasing the amount of acompound or dose x introduced into a system. Absorption studies seek todefine the rate of input, dx/dt, of the dose x. For example, a constantrate infusion, R, of a drug might be 1 mg/hr, while the integral overtime of dx/dt is referred to as the extent of drug input, x(t), i.e.,the total amount of drug x administered up to that particular time t.Complex absorption profiles can be created by the use of controlled,extended, delayed or timed release of drugs from a dosage form.

Disposition is further subdivided into the study of the absorption,distribution, metabolism and elimination or excretion of a drug,collectively referred to as ADME.

The processes of disposition can be seen as the clearing, or disposingof drug. Generally, the disposition process distributes the drug withinthe system, converts or metabolizes the drug, and eliminates the drug ormetabolites of the drug by passing them via the urine, feces, sweat,exhalation or other routes of elimination.

In one embodiment, the parenteral dosage forms of the present inventionprovide for the maintenance of a nocturnal rise in plasma prolactinlevel (a neuroendocrine physiological event) in obese/insulin resistantor type 2 diabetic subjects.

The ADME criteria influence the levels and kinetics of drug exposure tothe tissues and hence influence the performance and pharmacologicalactivity of a drug. Before an active agent can exert a pharmacologicaleffect in tissues, it has to be absorbed into the bloodstream. Theactive agent must then be distributed to its effector site(s), mostoften via the bloodstream. Active agents begin to be metabolized as soonas they enter the body. Compounds and their metabolites need to beexcreted from the body via excretion, usually through the kidneys(urine) or in the feces. Unless excretion is complete, accumulation offoreign substances can adversely affect normal metabolism.

In one embodiment, a dosage form exhibits a pharmacokinetic profile witha T_(max) about 1 to about 90 minutes or about 5 to about 90 minutesafter administration, a plasma drug concentration of at least 50%C_(max) for a duration of about 90 to about 360 minutes, and a decreasein plasma level that may approximate first order elimination kinetics.

In another embodiment, a dosage form exhibits a pharmacokinetic profilewith a T_(max) about 1 to about 90 minutes or about 5 to about 90minutes after administration, a plasma drug concentration of at least50% C_(max) for a duration of about 180 to about 360 minutes, and adecrease in plasma level that may approximate first order eliminationkinetics.

In a another embodiment, a dosage form exhibits a pharmacokineticprofile with a T_(max) about 1 to about 90 minutes or about 5 to about90 minutes after administration, a plasma drug concentration of about 70to 100% C_(max) for a duration of about 90 to about 360 minutes, and adecrease in plasma level that may approximate first order eliminationkinetics.

In a preferred embodiment, a dosage form exhibits a pharmacokineticprofile with a T_(max) about 1 to about 90 minutes or about 5 to about90 minutes after administration, a plasma drug concentration of at least70 to 100% C_(max) for a duration of about 180 to about 360 minutes, anda decrease in plasma level that may approximate first order eliminationkinetics.

In another embodiment, a dosage form exhibits a pharmacokinetic profilewith a T_(max) about 1 to about 90 minutes or about 5 to about 90minutes after administration, a post C_(max) level of about 35-65% ofC_(max) within about 30-150 minutes after T_(max), followed by a postC_(max) level of about one-half C_(max) for about 60 to 420 minutes,followed by a decrease in plasma level that may approximate first orderelimination kinetics.

Preferably, a pharmacokinetic profile has a T_(max) about 15 to about 90minutes after administration, a post C_(max) level of about 35-65% ofC_(max) within about 30-90 minutes after T_(max), followed by a postC_(max) level of about one-half C_(max) for about 60 to 360 minutes,followed by a decrease in plasma level that may approximate first orderelimination kinetics.

In another embodiment, a dosage form exhibits a pharmacokinetic profilehaving a plasma T_(max) about 15 to about 60 minutes afteradministration, a post C_(max) level of about one-half C_(max) withinabout 30 to about 150 minutes of T_(max) followed by a post C_(max)level of about one-half C_(max) for a duration of about 90 to about 360minutes, followed by a decrease in plasma level that may approximatefirst order elimination kinetics.

In yet another embodiment, a dosage form exhibits a pharmacokineticprofile with a plasma T_(max) about 10 to about 60 minutes afteradministration, a post C_(max) level of about one-half C_(max) withinabout 30 to about 150 minutes of T_(max), a post C_(max) level of aboutone-half C_(max) for a duration of about 90 to about 240 minutes, and adecrease in plasma level that may approximate first order eliminationkinetics.

In one embodiment, a dosage form exhibits a pharmacokinetic profile witha plasma T_(max) about 5 to about 60 minutes after administration, aplasma T_(max) 10 to 60 minutes after administration, a plasma T_(max)10 to 90 minutes after administration, a plasma T_(max) 15 to 90 minutesafter administration, or a plasma T_(max) 15 to 60 minutes afteradministration.

In one embodiment, a dosage form exhibits a pharmacokinetic profile with90% of the active agent cleared from plasma within about 240 to about480 minutes from the end of the post C_(max) level.

In one embodiment, a dosage form exhibits a pharmacokinetic profile withsubstantially all of the active agent cleared from plasma within about 5hours following the end of the plasma plateau.

In one embodiment, a dosage form exhibits a pharmacokinetic profilewherein the post-C_(max) plateau is sustained for about 2 to about 8hours.

In one embodiment, more than about 10% of the total active agent of adosage form is absorbed into the plasma. In another embodiment, morethan about 35% of the total active agent of a dosage form is absorbedinto the plasma.

In one embodiment, a permeability enhancer is combined in one portion ofthe dosage form with a sustained release mechanism in another portion ofthe dosage form to allow for the quick peak followed by the sustained“tail” of the pharmacokinetic profile of the formulation.

The above described pharmacokinetic profiles allow for a peak ofdopamine agonist into the circulation that can be used to impact acircadian neuro-oscillator system (e.g., suprachiasmatic nucleus) in thebrain to positively influence its regulation of metabolism via outputcontrol over other metabolism regulatory centers in the brain to therebyimprove peripheral metabolism immediately followed by a sustained lowerlevel of release of dopamine agonist into the circulation for adetermined period of time that can directly influence other metabolismregulatory centers in the brain to improve metabolism.

Some of the above described pharmacokinetic profiles allow for a pulsedpeak of dopamine agonist into the circulation that can be used to impacta circadian neuro-oscillator system (e.g., suprachiasmatic nucleus) inthe brain followed by a sustained lower level of release of dopamineagonist into the circulation for a determined period of time.

When used at the appropriate dosages and pre-determined times of day inan individual with metabolic disease, the above describedpharmacokinetic profiles can mimic the natural daily pattern of braindopamine in metabolic control centers within the brain of a healthynormal individual of the same species and thereby improve metabolicdisease.

Thus, a dosage form according to the present invention may exhibit apharmacokinetic profile having a plasma T_(max) followed by a postC_(max) level of at least that is 70 to 100% for a sustained period oftime prior a decrease in plasma level that may approximate first orderelimination kinetics. See e.g., FIG. 1. Alternatively, a dosage formaccording to the present invention may exhibit a pharmacokinetic profilehaving a plasma T_(max), followed by a post C_(max) level that decreasesover time to about one-half C_(max), a decreased level and that is thensustained for a period of time prior to a decrease in plasma level thatmay approximate first order elimination kinetics. See e.g., FIG. 2.

When one or more dopamine agonist is administered with a peripheralacting agent, the one or more dopamine agonist and the peripheral actingagent may, have the same pharmacokinetic profile or substantiallysimilar or similar pharmacokinetic profiles, e.g., any of thepharmacokinetic profiles set forth above. Alternatively, when one ormore dopamine agonist is administered with a peripheral acting agent,the one or more dopamine agonist and the peripheral acting agent may,have different pharmacokinetic profiles. In certain embodiments, forexample, the one or more dopamine agonist has a pharmacokinetic profileset forth above and a peripheral acting agent has a pharmacokineticprofile having a T_(max) between 0-90 min with a plasma levelconcentration of greater than or equal to about 25% of C_(max) from thetime of T_(max) through 12 hours post T_(max).

The particular pharmacokinetic profile produced by a dosage formaccording to the present invention will vary, in part, based on theamount of active agent included in the dosage formulation.

In certain embodiments, a dosage form includes bromocriptine as theactive agent and exhibits one of the foregoing pharmacokinetic profiles,more preferably with a C_(max) of 25-400 pg/ml.

Moreover, it will be appreciated by those skilled in the art that thedesired in vitro dissolution rate, and/or the in vivo plasmaconcentration of dopamine agonists over time, may be obtained byselecting one or more forms of dopamine agonist, i.e., selecting one ormore salt forms, crystalline forms (including one or more polymorphicforms) or amorphous forms for use in the immediate or controlled releasecompositions of the present invention.

Administration

The amount of the dopamine agonist(s) to be administered to a patientmay vary depending for example on the weight of the patient, and thenature or severity of the metabolic disease or the key elements thereof.An effective amount of the dopamine agonist(s) may be administered inone or more dosage forms, either simultaneously or at different times,and a dopamine agonist may be administered either separately or inconjunction with other dopamine agonist(s).

Preferably, the dosage forms may be administered in a single daily doseof about 0.01 to about 50.0 mg of active agent. The preferred range is0.02 to 50 mg of active agent, the more preferred range is 0.02 to 25 mgof active agent and the most preferred range is 0.1 to 25 mg of activeagent.

Conjoined administration of one or more dopamine D₁ agonist with one ormore D₂ agonist results in synergistic effects in improvement of one ormore metabolic indices related to glucose or lipid metabolism, and thusan improved modification or regulation of at least one of glucose andlipid metabolism.

The administration of the D₂ agonist is preferably timed. The D₂ agonistcan be administered at a pre-determined time.

The administration of the D₁ agonist is preferably timed. The D₁ agonistis administered at a pre-determined time. Because the D₁ agonistamplifies the effect of the conjoined D₂ agonist, it is advantageous toadminister the D₁ agonist at or about the time of administration of theconjoined D₂ agonist(s), such that the activity period of the D₁ agonistin the bloodstream of the treated subject overlaps (in fact preferablyoverlaps as much as possible) with the activity period of the conjoinedD₂ agonist(s). The duration of the post-Tmax plasma plateau level of theD1 agonist may persist for a period of time longer than that of the D2agonist. For convenience of administration and in order to promotesubject compliance, the D₁ agonist can be administered at the same timeas the conjoined D₂ agonist(s).

Preferably, the dosage form(s) are administered once daily. Morepreferably, the dosage form(s) are administered once daily in themorning. Most preferably, the dosage form(s) are administered once dailyat a pre-determined time for bioavailability in the morning at a pointafter the peak in plasma prolactin level.

Dosage forms are preferably administered in the morning from about 0400to about 1200 hours. More preferably, the dosage forms are administeredin the morning from about 0500 to about 1200 hour. Most preferably, thedosage forms are administered in the morning from about 0500 to about1000 hour.

For treating vertebrates, dosages of dopamine agonists are typicallyadministered over a period ranging from about 10 days to about 180 days,or longer (e.g., greater than or equal to 1 year). However, patients,e.g., patients in particularly poor physical condition, or those ofadvanced age, may require longer, or even continuous, treatment. Atreatment duration exceeding six months or even continuous treatment maybe desirable, even when not required.

Administration of D₁ and D₂ agonists typically lead to improvement of atleast one condition or indices indicative of a metabolic disorder. Thus,in some embodiments administration of D₁ and D₂ agonist lead to areduction of one or more of a metabolic disorder and/or key elementsthereof such as body fat deposits, body weight, plasma or blood glucose,circulating insulin, plasma triglycerides (TG), plasma free fatty acids(FFA), cardiometabolic risk factors such as cardiovascular-relatedinflammatory factors, potentiators of vascular endothelial dysfunction,and hypercoagulative substances including but not limited to PAI-1 orfibrinogen, blood clotting rate or potential, neuroendocrine factorspotentiating insulin resistance, blood pressure, renal dysfunctionand/or insufficiency, and food consumption.

In other embodiments, the parenteral dosage forms of the presentinvention provide for one or more of the following metabolicphysiological events in metabolic syndrome, obese, obese/insulinresistant, prediabetic, or type 2 diabetic subjects: (1) improvement ofhyperglycemia, hypertriglyceridemia, impaired fasting glucose, glucoseintolerance, or insulin resistance; (2) improvement in hypertension; (3)reduction of physiological indices of cardiovascular inflammation,endothelial dysfunction, hypercoagulation or blood clotting; and/or (4)reduction of body fat stores or body weight or both (5) improvement ofrenal function or (6) improvement of cardiac function.

In a certain embodiment, the parenteral dosage forms allow for anocturnal (0200-0600 hour) increase in plasma prolactin of at least 35%greater than the average diurnal (0700-1900 hour) circulating level ofthe hormone following early morning administration of such dopamineagonist pharmaceutical preparation measured at least 6 months after theinitiation of such treatment.

In a certain embodiment, the elevated (at least 15% greater than averagefor a normal healthy individual of the same age and sex) plasmanorepinephrine levels are reduced by at least 10% by such treatment. Inone embodiment, elevated plasma norepinephrine levels are reduced by atleast 15%.

In a certain embodiment, nocturnal plasma prolactin levels are at least35% greater than the average diurnal circulating level of prolactinfollowing such dopamine agonist treatment when measured at 6 months fromthe initiation of the treatment.

In a certain embodiment, the parenteral dosage forms do not produceuntoward GI effects, e.g., nausea, vomiting, abdominal pain,constipation, and/or diarrhea, in more than 15% of the treatedpopulation.

In a certain embodiment, the dosage form includes bromocriptine andother ergot derivatives and produces a circulating concentration ofmetabolites that is no greater than about 50% of that metaboliteconcentration produced by an oral dose of bromocriptine (or other ergotderivatives) that produces the same circulating level of bromocriptine(or other ergot derivatives).

Preparation of Dosage Forms

Water and light can accelerate the degradation of ergot-type compoundsby photooxidation, photoreduction, redox reactions involving water(e.g., breakdown of bromocriptine into bromocriptinine upon excessivewater or humidity exposure). Thus, the preparation of stable parenteraldosage forms comprising ergot-related dopamine agonists should beconducted to minimize exposure to light and absorption of water.

Where the production of the dosage forms of the invention which can beadministered parenterally has not taken place under aseptic conditions,a final sterilization can be carried out by conventional methods knownto the skilled worker, for example by autoclaving or sterile filtering.The suspensions of the invention which can be administered parenterallyhave preferably been produced under aseptic conditions.

Other formulation techniques may be performed using techniques wellknown in the art. The following examples of such techniques areillustrative and are not intended to be limiting.

Magnesium stearate and stearic acid should be added last to formulationsand blended for 2 min. Magnesium should be avoided for the preparationof ergot-related dopamine agonist formulations inasmuch as magnesiumgreatly decreases their stability.

Particular dosage forms may be prepared using procedures well known inthe art. For all embodiments, the components are given as percentage oftotal weight. The following are non-limiting guidelines for preparingcertain types of dosage forms:

Injectable or Liquid Dosage Form

A dopamine agonist is dissolved in non-aqueous solvent or is incolloidal suspension of small aggregate size in vessel one and dopamineagonist in colloidal suspension of larger aggregate size than in vesselone (including but not necessarily limited to micronized dopamineagonist) in liquid carrier in vessel two at a total amount of 0.02 to50.0 mg.

Vessel one may contain varying amounts of non-aqueous solvent such asethanol, isopropanol, or propanol at 10 to 50 μl. To this solution asmall volume (about 25% of solution volume) of anhydrous mucosal tissueirritant-reducing agent such as plant oils like but not limited to oliveoil, corn oil or mineral oil is added.

Optionally, the solution in vessel one is then combined with anhydrouspermeabilizing agents, bioadhesives, polymers, and/or stabilizers (e.g.,antioxidants such as citric acid, or ascorbic acid) to give a finalvolume of solution of not greater than 100 μl.

Vessel two may contain either aqueous or non-aqueous solvent such asethanol, isopropanol, or propanol at 10 to 50 μl.

To this solution a small volume (about 25% of solution volume) ofanhydrous mucosal tissue irritant-reducing agent such as plant oils likebut not limited to olive oil, corn oil or mineral oil is added.

Optionally, the solution in vessel two is then combined with anhydrouspermeabilizing agents, bioadhesives, polymers, and/or stabilizers (e.g.,antioxidants such as citric acid, or ascorbic acid) to give a finalvolume of solution of not greater than 100 μl.

Aerosol Dosage Form

Aerosol dosage forms may generally be prepared by adding an inert gas(e.g., nitrogen) to a liquid dosage form.

Aerosol Dosage Form

A dopamine agonist is solubilized in non-aqueous solvent such asanhydrous ethanol in a low humidity environment optionally combined witha mucosal tissue irritant-reducing agent and then placed in one chamberof a metal or hard plastic canister that is pressurized with an inertgas such as nitrogen. The canister is equipped with a mechanism formetered dosing in an aerosol spray form or the like in the range of 5 to100 μl per dose. Optionally, after solubilization in ethanol as above,permeabilizing agents (such as bile salts, surfactants, fatty acids andderivatives, chelators, cyclodextrins, chitosan, lower alcohols),bioadhesives (such as Carbopol 934P, Carbopol 974P, 1Voveou AA-1,polyvinylpyrrolidone), and/or stabilizers such as polyethylene glycolknown in the art to facilitate mucosal delivery of dopamine agonist tothe systemic circulation through the mucosal site of administration areadded to the dopamine agonist solution. Additionally, a quantity ofanhydrous polymer such as polyethylene glycol to improve solubility ofthe solute components and reduce the ethanol concentration is added tothe dopamine agonist-ethanol solution.

In a second separate chamber of the same canister, the dopamine agonistis micronized and added to an appropriate solvent vehicle such aspolyethylene glycol to form a colloidal suspension. To such colloidalsuspension permeabilizing agents, bioadhesives, and/or stabilizers knownin the art that either are soluble in the vehicle or form a colloidalsuspension as well are added. Such dopamine agonist suspension is placedin a metal or hard plastic canister for spray administration under inertgas pressurization.

Aerosol Dosage Form

Dopamine agonist is added to solvent at a concentration of 0.1 to 5.0 mgper approximately 10-50 μl of either an aqueous or non-aqueous solventsuch as ethanol. To the solution is added a small volume (25% ofsolution volume) of mucosal tissue irritant-reducing agent such as oliveoil or mineral oil. Optionally, mucosal uptake enhancers such as freefatty acid, and/or bioadhesives such as polyvinylpyrrolidone are addedto this mixture. The solution is mixed until the dopamine agonist isfully dissolved and then the solution is placed into a lightimpenetrable device that is pressurized under inert gas such as nitrogenand equipped with a mechanism for metered delivery of 10 to 100 μl sprayper dosing to provide a dose of 0.1 to 5.0 mg dopamine agonist.

In a second separate chamber of the same device, dopamine agonist isadded to either an aqueous or non-aqueous solvent, such as anhydrousethanol in a low humidity environment at a concentration of 0.1 to 50.0mg per approximately 5-25 μl of ethanol. Upon full dissolution of thedopamine agonist into the solvent a polymer such as polyethylene glycol,or long chain fatty acids or plant oil such as olive oil, corn oil, ormineral oil is added to produce an approximate 70/30 solution ofethanol/other agent to adjust the absorption rate of dopamine agonist ofthis preparation to be different from (slower than) that of thepreparation of the other chamber of the canister. To the solution, isadded a small volume (25% of solution volume) of mucosal tissueirritant-reducing agent such as olive oil or mineral oil. To thissolution are added mucosal uptake enhancers such as free fatty acid,and/or bioadhesives such as polyvinylpyrrolidone. The solution is mixeduntil the dopamine agonist is fully dissolved or prepared as a colloidalsuspension and then the solution is placed into a light impenetrabledevice that is pressurized under inert gas such as nitrogen and equippedwith a mechanism for metered delivery of 10 to 50 μl spray per dosing toprovide a dose of 0.1 to 50.0 mg dopamine agonist.

Aerosol or Liquid Dosage Form

Dopamine agonist is micronized to a diameter of between 0.1 and 1.0 μmand then added to a polymer such as polyethylene glycol or to fattyacid, or to a plant oil such as mineral oil or the like to form acolloidal suspension of 0.1 to 5.0 mg of dopamine agonist per 10-50 μlof vehicle. To the suspension a small volume (25% of suspension volume)of mucosal tissue irritant-reducing agent such as olive oil or mineraloil is added. To this suspension mucosal uptake enhancers such as freefatty acid, and/or bioadhesives such as polyvinylpyrrolidone is added.The suspension is placed into a light impenetrable device that ispressurized under inert gas such as nitrogen and equipped with amechanism for metered delivery of 10 to 100 μl spray per dosing toprovide a dose of 0.1 to 5.0 mg dopamine agonist.

In a second separate chamber of the same device, dopamine agonist isadded to either an aqueous or non-aqueous solvent such as anhydrousethanol in a low humidity environment at a concentration of 0.1 to 50.0mg per approximately 5-25 μl of ethanol. Upon full dissolution of thedopamine agonist into the solvent a polymer such as polyethylene glycol,or long chain fatty acids or plant oil such as olive oil, corn oil, ormineral oil is added to produce an approximate 70/30 solution ofethanol/other agent to adjust the absorption rate of dopamine agonist ofthis preparation to be different from (slower than) that of thepreparation of the other chamber of the canister. To the solution, isadded a small volume (25% of solution volume) of mucosal tissueirritant-reducing agent such as olive oil or mineral oil. To thissolution are added mucosal uptake enhancers such as free fatty acid,and/or bioadhesives such as polyvinylpyrrolidone. The solution is mixeduntil the dopamine agonist is fully dissolved or prepared as a colloidalsuspension and then the solution is placed into a light impenetrabledevice that is or is not pressurized under inert gas such as nitrogenand equipped with a mechanism for metered delivery of 10 to 100 μl sprayper dosing to provide a dose of 0.1 to 50.0 mg dopamine agonist.

Solid Dosage Form

A solid stable parenteral dosage form of the present invention isprepared that includes: (1) a dopamine agonist having from 0.02 to 50.0mg of small particle size, and having a relatively larger particle sizefor slower dissolution and absorption; mixed with an antioxidant such ascitric acid (2); the mixture is combined with a carrier such as mannitoland then combined with a disintegrant and bioadhesive such as Benecal orKollidon CL and an anhydrous polymer as binder such as cellulose orcellulose analogs, polyethyleneglycol, fatty acid, or plant oil; (3)optionally, a small amount of anhydrous mucosal tissue irritant-reducingagent such as olive oil or mineral oil; and (4) optionally, additionalanhydrous permeabilizing agents, bioadhesives, and/or stabilizers areadded followed by a lubricant such as stearate or castor oil to give afinal weight of not greater than 200 mg to produce a rapid dissolvingsolid dosage form with rapid and slower sustained absorption of dopamineagonist wherein final dosage is between 0.02 and 50.0 mg. Theseingredients are preferably added to the mixture in this order.

Solid Dosage Form

A solid stable parenteral dosage form of the present invention isprepared that includes: (1) micronized dopamine agonist of diameter (a)0.1 to 5.0 μm and (b) 10-200 μm at 0.02 to 50.0 mg total; mixed with anantioxidant such as citric acid (2); the mixture is combined with acarrier such as mannitol and then combined with a disintegrant andbioadhesive such as Kollidon CL and an anhydrous polymer as binder suchas cellulose or cellulose analogs, polyethyleneglycol, fatty acid, orplant oil; (3) optionally, a small amount of anhydrous mucosal tissueirritant-reducing agent such as olive oil or mineral oil; and (4)optionally, additional anhydrous permeabilizing agents, bioadhesives,and/or stabilizers are added followed by a lubricant such as stearate orcastor oil to give a final weight of not greater than 250 mg to producea rapid dissolving solid dosage form with rapid and slower sustainedabsorption of dopamine agonist wherein final dosage is between 0.02 and50.0 mg. These ingredients are preferably added to the mixture in thisorder.

Solid Dosage Form

Dopamine agonist is added to either an aqueous or anhydrous solvent suchas ethanol in a low humidity environment at a concentration of 0.1 to50.0 mg per approximately 50-250 μl of solvent. Upon full dissolution ofthe dopamine agonist into the solvent a polymer such as polyethyleneglycol or a fatty acid or a plant oil is added to produce an approximate70/30 solution of solvent/other agent. To the solution is added a smallvolume (25% of solvent volume) of mucosal tissue irritant-reducing agentsuch as olive oil or mineral oil. To this solution are added mucosaluptake enhancers such as free fatty acid, and/or bioadhesives such aspolyvinylpyrrolidone. The dopamine agonist-solution may then be combinedwith a binder or matrix such as plant gum, gelatin,polyvinylpyrrolidone, magnesium stearate, or castor oil providing forrapid dissolution, dried and then formed into one side of a solid dosageform at 0.1 to 50.0 mg per dosage for mucosal delivery.

A second portion of the solid dosage form is comprised of (1) micronizeddopamine agonist of diameter 0.1 to 5.0 μm or small particle sizedopamine agonist of 10-200 um at 0.02 to 50.0 mg total; mixed with anantioxidant such as citric acid; (2) the mixture is combined with acarrier such as mannitol and then combined with a disintegrant andbioadhesive such as Kollidon CL and an anhydrous polymer as binder suchas cellulose or cellulose analogs, polyethyleneglycol, fatty acid, orplant oil; (3) optionally, a small amount of anhydrous mucosal tissueirritant-reducing agent such as olive oil or mineral oil; and (4)optionally, additional anhydrous permeabilizing agents, bioadhesives,and/or stabilizers are added followed by a liquid matrixing agent suchas polyvinylpyrrolidone, gelatin, or plant gum that is dried to give afinal weight of not greater than 250 mg to produce a rapid dissolvingsolid dosage form with rapid and slower sustained absorption of dopamineagonist wherein the final dosage is between 0.02 and 50.0 mg. Theseingredients are preferably added to the mixture in this order. The twosections of the dosage form are annealed and packaged into an aluminumfoil wrap to prevent moisture from entry. Alternatively the two sectionsare combined, one inside of the other for delivery that effectuates afast absorption and a slower more sustained absorption.

Solid Dosage Form

Dopamine agonist is micronized to a diameter of between 0.1 and 1.0 μmand then added to an anhydrous polymer such as polyethylene glycol or tofatty acid or to a plant oil to form a colloidal suspension of 0.1 to1.0 mg of dopamine agonist per 10-25 μl of vehicle. To the suspension isadded a small volume (25% of suspension volume) of mucosal tissueirritant-reducing agent such as olive oil or mineral oil. To thissuspension are added mucosal uptake enhancers such, as free fatty acid,and/or bioadhesives such as polyvinylpyrrolidone. The dopamine agonistsuspension is then combined with a binder or matrix such as plant gum,gelatin, mannitol, polyvinylpyrrolidone, or stearate. The dopamineagonist-colloidal suspension may then be combined with a binder ormatrix such as plant gum, gelatin, polyvinylpyrrolidone, stearate, orcastor oil providing for rapid dissolution, dried and then formed intoone side of a solid dosage form at 0.1 to 50.0 mg per dosage for mucosaldelivery.

A second portion of the solid dosage form is comprised of (1) smallparticle size dopamine agonist of 10-200 μm at 0.02 to 50.0 mg totalmixed with an antioxidant such as citric acid; (2) the mixture iscombined with a carrier such as mannitol and then combined with adisintegrant and bioadhesive such as Kollidon CL and an anhydrouspolymer as binder such as cellulose or cellulose analogs,polyethyleneglycol, fatty acid, or plant oil; (3) optionally, a smallamount of anhydrous mucosal tissue irritant-reducing agent such as oliveoil or mineral oil; and (4) optionally, additional anhydrouspermeabilizing agents, bioadhesives, and/or stabilizers are addedfollowed by a liquid matrixing agent such as polyvinylpyrrolidone,gelatin, or plant gum that is dried to give a final weight of notgreater than 250 mg to produce a rapid dissolving solid dosage form withrapid and slower sustained absorption of dopamine agonist wherein thefinal dosage is between 0.02 and 50.0 mg. These ingredients arepreferably added to the mixture in this order. The two sections of thedosage form are annealed and packaged into an aluminum foil wrap toprevent moisture from entry. Alternatively the two sections may becombined, one inside of the other for delivery that effectuates a fastabsorption and a slower more sustained absorption.

Solid Tablet Dosage Form

According to one embodiment, a solid sublingual tablet dosage formcomprises one or more active agents, about 3-50% release matrix, about0.5-10% glidant, up to about 70% solubility enhancer, up to about 25%bioadhesion enhancer, up to about 30% permeation enhancer, up to about95% disintegrant, up to about 95% filler, and up to about 65%effervescent.

In another embodiment, a solid sublingual tablet dosage form comprisesone or more active agents, about 3-20% release matrix, about 0.5-5%glidant, up to about 30% solubility enhancer, up to about 10%bioadhesion enhancer, up to about 20% permeation enhancer, up to about85% disintegrant, up to about 80% filler, and up to about 45%effervescent.

In a preferred embodiment, a solid sublingual tablet dosage formcomprises one or more active agents, about 7-15% release matrix, about0.5-2.5% glidant, about 2-20% solubility enhancer, about 2-8%bioadhesion enhancer, up to about 15% permeation enhancer, up to about82% disintegrant, up to about 75% filler, and up to about 45%effervescent.

In a further embodiment, a solid sublingual tablet dosage form comprisesone or more active agents, about 5-10% release matrix, about 0.5-2%glidant, about 1-5% solubility enhancer, about 2-8% bioadhesionenhancer, up to about 15% permeation enhancer, up to about 12%disintegrant, and up to about 75% filler.

According to another embodiment, a solid sublingual tablet dosage formcomprises one or more active agents, about 5-10% release matrix, about0.5-2% glidant, about 1-5% solubility enhancer, about 2-8% bioadhesionenhancer, up to about 15% permeation enhancer, up to about 12%disintegrant, and up to about 75% filler.

According to one embodiment, a solid sublingual tablet dosage formcomprises one or more active agents, about 5-10% release matrix, about0.5-2% glidant, about 1-5% solubility enhancer, about 2-8% bioadhesionenhancer, about 75-85% disintegrant, up to about 15% permeationenhancer, and up to about 75% filler.

In another embodiment, a solid sublingual tablet dosage form comprisesone or more active agents, about 3-20% release matrix, about 0.5-5%glidant, about 0.5-10% solubility enhancer, about 2-15% bioadhesionenhancer, about 3-25% disintegrant, up to about 30% permeation enhancer,and about 3-85% filler.

In another embodiment, a solid sublingual tablet dosage form comprisesone or more active agents, about 5-10% release matrix, about 0.5-2%glidant, about 1-5% solubility enhancer, about 2-8% bioadhesionenhancer, about 60-80% disintegrant, and up to about 15% permeationenhancer.

In a further embodiment, a solid sublingual tablet dosage form comprisesone or more active agents, about 3-10% release matrix, about 0.5-5%glidant, about 1-6% solubility enhancer, about 2-6.5% bioadhesionenhancer, about 60-90% disintegrant, and up to about 30% permeationenhancer.

According to another embodiment, a solid sublingual tablet dosage formcomprises one or more active agents, about 3-10% release matrix, about0.5-5% glidant, about 1-10% solubility enhancer, about 2-10% bioadhesionenhancer, about 60-90% disintegrant, and up to about 30% permeationenhancer.

According to another embodiment, a solid sublingual tablet dosage formcomprises one or more active agents, about 10-20% release matrix, about0.5-2% glidant, about 15-25% solubility enhancer, about 8-15%bioadhesion enhancer, about 6-12% disintegrant, and about 35-45%effervescent.

According to a further embodiment, a solid sublingual tablet dosage formcomprises one or more active agents, about 5-35% release matrix, about0.5-5% glidant, about 10-40% solubility enhancer, about 5-25%bioadhesion enhancer, about 3-25% disintegrant, and about 10-65%effervescent.

According to a further embodiment, a solid sublingual tablet dosage formcomprises about 0.5-5% active agents, about 3-20% release matrix, about0.5-5% glidant, about 0.5-10% solubility enhancer, about 2-15%bioadhesion enhancer, about 3-25% disintegrant, about 40-95% filler, andoptionally about 5-30% permeation enhancer.

In a further embodiment, a solid sublingual tablet dosage form comprisesabout 0.5-4.5% active agents, about 3-10% release matrix, about 0.5-5%glidant, about 1-6% solubility enhancer, about 2-6.5% bioadhesionenhancer, about 60-90% disintegrant, and optionally about 5-30%permeation enhancer.

According to another embodiment, a solid sublingual tablet dosage formcomprises about 1-6% active agents, about 3-10% release matrix, about0.5-5% glidant, about 1-10% solubility enhancer, about 2-10% bioadhesionenhancer, about 60-90% disintegrant, and optionally about 5-30%permeation enhancer.

According to a further embodiment, a solid sublingual tablet dosage formcomprises about 0.5-5% active agents, about 5-35% release matrix, about0.5-5% glidant, about 10-40% solubility enhancer, about 5-25%bioadhesion enhancer, about 3-25% disintegrant, and about 10-65%effervescent.

For the aforementioned dosage forms: the preferred release matrixcomponents are Carbopol 974, Benecel, or Xanthan gum or a mix thereof;the preferred glidants are magnesium sterate and stearic acid; thepreferred solubility enhancers are citric acid and ascorbic acid; thepreferred bioadhesion enhancer is polyvinyl pyrrolidone; the preferreddisintegrants are Pharmaburst and Explotab (sodium starch glycolate andsodium carboxymethyl starch); the preferred fillers are Cab-o-Sil,granular mannitol, and microcrystalline cellulose such as ProSolv; andthe preferred effervescent is Effersoda-12.

For the aforementioned dosage forms: the more preferred release matrixcomponent is Benecel; the more preferred glidants is stearic acid; themore preferred solubility enhancer is citric acid; the more preferredbioadhesion enhancer is polyvinyl pyrrolidone; the more preferreddisintegrant is Pharmaburst; the more preferred fillers are granularmannitol and microcrystalline cellulose such as ProSolv; and the morepreferred effervescent is Effersoda-12.

According to one preferred embodiment, a solid sublingual tablet dosageform comprises about 0.5-5% dopamine agonist, about 3-20%hydroxypropylmethylcellulose, about 0.5-5% steric acid, about 0.5-10%citric acid, about 2-15% PVP, about 3-25% sodium starch glycolate andsodium carboxymethyl starch, about 40-80% mannitol, and about 3-25%ProSolv.

According to another preferred embodiment, a solid sublingual tabletdosage form comprises about 0.5-5% dopamine agonist, about 3-20%hydroxypropylmethylcellulose, about 0.5-5% steric acid, about 0.5-10%citric acid, about 2-15% PVP, about 3-25% sodium starch glycolate andsodium carboxymethyl starch, about 40-80% mannitol, about 3-25% ProSolv,and about 5-30% cyclodextrin.

According to another preferred embodiment, a solid sublingual tabletdosage form comprises about 0.5-4.5% dopamine agonist, about 3-10% HPMC,about 0.5-5% steric acid, about 1-6% citric acid, about 2-6.5% PVP, andabout 60-90% Pharmaburst.

According to a further preferred embodiment, a solid sublingual tabletdosage form comprises about 0.5-4.5% dopamine agonist, about 3-10% HPMC,about 0.5-5% steric acid, about 1-6% citric acid, about 2-6.5% PVP,about 60-90% Pharmaburst, and about 5-30% cyclodextran.

According to a further preferred embodiment, a solid sublingual tabletdosage form comprises about 1-6% dopamine agonist, about 3-10% HPMC,about 0.5-5% steric acid, about 1-10% citric acid, about 2-10% PVP, andabout 60-90% Pharmaburst.

According to a further preferred embodiment, a solid sublingual tabletdosage form comprises about 1-6% dopamine agonist, about 3-10% HPMC,about 0.5-5% steric acid, about 1-10% citric acid, about 2-10% PVP,about 60-90% Pharmaburst, and about 5-30% cyclodextran.

According to a further preferred embodiment, a solid sublingual tabletdosage form comprises about 0.5-5% dopamine agonist, about 5-35% HPMC,about 0.5-5% steric acid, about 10-40% citric acid, about 5-25% PVP,about 3-25% Pharmaburst, and about 10-65% Effersoda-12 or sodiumbicarbonate.

Transdermal Gel Dosage Form

Transdermal gel formulations of the present invention are prepared bydissolving a dissolving a stabilizer (e.g., antioxidants such as citricacid, or ascorbic acid) in a surfactant such as lauric acid, oleic acid,stearic acid, myristic acid, ricinoleic acid, or polyethylene glycol.Add an additional non-aqueous solvent (e.g., propylene glycol, glycerol,short-chain substituted or non-substituted alcohols such as ethanol,isopropanol, or propanol) and sonicated. Optionally a bioadhesive/activeagonist release matrix can be added to the non-aqueous solvent beforesonication. A permeabilizing agents (e.g., bile salts, fatty acids,fatty acid derivatives, fatty acid esters, enamine derivatives andalpha-keto aldehydes, sodium cholate, sodium glycocholate, sodiumdeoxycholate, sodium lauryl sulfate, sodium salicylate, sodiumethylenediaminetetraacetic acid (EDTA), aprotinin, azone, sodium5-methoxysalicylate, 1-oleylazacycloheptan-2-one, and/or silicas with ahigh affinity for aqueous solvents, such as the precipitated silicabetter known by the trade mark Syloid®, maltodextrins, β-cyclodextrins,surfactants, chelators, cyclodextrins, chitosan, and lower alcohols) isgradually added to the solution with the help of manual stirring andsonication.

The resulting slurry is pushed though a size 40 stainless steel meshsieve. The milky creamy suspension (the stock solution slowly separatedafter several days of subsequent storage in the refrigerator) is addedto the polypropylene mixture and sonicated for 5 min. Permeabilizingagents are gradually added to solution, with a help of manual stirringand sonication.

Transdermal Gel Dosage Form

According to one embodiment, the transdermal gel dosage form comprisesone or more active agents, about 5-95% solvents, about 1-30% thickener,about 0.5-10% stabilizer, and up to about 35% bioadhesive enhancers.

In another embodiment, a transdermal gel dosage form comprises one ormore active agents, about 5-90% solvents, about 5-12% thickener, andabout 0.5-1.5% stabilizer.

In a further embodiment, the transdermal gel dosage form comprises oneor more active agents, about 5-90% solvents, about 3-25% thickener,about 0.5-30% bioadhesive enhancers and about 0.5-5% stabilizer.

In a further embodiment, a transdermal gel dosage form comprises one ormore active agents, about 5-90% solvents, about 3-25% thickener, andabout 0.5-5% stabilizer.

In a further embodiment, a transdermal gel dosage form comprises about0.5-10% active agents, about 50-95% solvents, about 3-25% thickener, andabout 0.5-5% stabilizer.

In a further embodiment, the transdermal gel dosage form comprises about0.5-10% active agents, about 50-95% solvents, about 3-25% thickener,about 1.5-30% bioadhesive enhancers and about 0.5-5% stabilizer.

For the aforementioned transdermal gel dosage forms: the preferredsolvents are propylene glycol and glycerol; the preferred thickener issilica 200; the preferred stabilizing agent is citric acid anhydrous,and the preferred bioadhesives are hydroxypropylmethylcellulose andpolyvinyl pyrrolidone.

In a preferred embodiment, a transdermal gel dosage form comprises about0.5-10% dopamine agonist, about 5-40% PEG, about 45-85% glycerol, about3-25% silica, and about 0.5-5% citric acid.

In another preferred embodiment, a transdermal gel dosage form comprisesabout 0.5-10% dopamine agonist, about 5-40% PEG, about 45-85% glycerol,about 3-25% silica, about 1-15% hydroxypropylmethylcellulose, about0.5-15% PVP, and about 0.5-5% citric acid.

Transdermal Patch Dosage Form

A solid stable parenteral dosage form of the present invention isprepared that includes: (1) dopamine agonist of dissolved state, singleor two different particle sizes at 0.02 to 5.0 μm; (2) nontoxic organicsolvent such as ethanol, isopropanol, propanol at 5 to 100 μl; and (3)optionally, anhydrous permeabilizing agent such as polyethyleneglycol orfatty acid, or plant oil is added.

The above formulation is then added to a transcutaneous drug deliverysystem.

The transcutaneous drug delivery system comprises: (1) a ratecontrolling matrix membrane, of polyethylene, polyurethane, PVC,polyacrylates, polycarbonates, polyvinyls, polystyrenes, polyamides, andderivatives thereof, cellulose, cellulose derivatives, and combinationsof the above, the thickness and porosity of which can be adjusted toadjust the diffusion rate of drug from the reservoir; and (2) anadhesive for adhering such drug matrix to the skin such that suchadhesive does not physically block the release of drug from the deliverysystem into the skin; (3) a backing impenetrable to light, moisture,humidity, and the contents of the delivery system; and (4) a removablefront impenetrable to light, moisture, humidity, and the contents of thedelivery system. The delivery system is further characterized by theability to have a slow and faster delivery rate to and through thecutaneous tissue for a respectively slow and faster absorption rate into the body.

Transepithelial Combination Formulation of Dopamine Agonist PlusPeripheral Acting Agent

Peripheral acting agents can be added to the slow release component ofdopamine agonist formulations. The peripheral acting agent then isreleased slowly from the formulation to provide a sustained release overan approximate 4-12 hour period of time from administration. In somecases where it may be desirable, the peripheral acting agent may also beadded to the fast release component of the dopamine agonist formulationto effectuate a fast release of peripheral acting agent. In still othercases, the peripheral acting agent may be added to both the slow andfast release components of the dopamine agonist formulation to produce arapid rise in the plasma followed by a sustained peak or near-peaklevels for an approximate 4-12 hour period.

Transmucosal Film Dosage Form

A solid stable film for sublingual or buccal administration of dopamineagonists is prepared with polyvinylpyrrolidones andpolyvinylpyrrolidones-polyvinyl acetate co-polymers. These polymersallow the use of a non-aqueous solvent as the only formulation solventrather than water. This is important when using particular dopamineagonists such as ergot related compounds, which are labile in water.

Moreover, it is possible to enhance bioavailability and to provide thedesired peak-plateau bioavailability curve of the present invention byadding additional permeation enhancers such as fatty acids andbioadhesives to the film formulation. Also, taste enhancers can be addedto the film formulation for a favorable taste.

Transmucosal Film Dosage Form

A Base Composition is prepared by adding polyvinylpyrrolidones such asKollidon 90F, Kollidon VA64, and a surfactant such as lauric acid, oleicacid, stearic acid, myristic acid, ricinoleic acid, or polyethyleneglycol to a non-aqueous solvent such as anhydrous ethanol. Optionally,an additional non-aqueous solvent (e.g., propylene glycol, glycerol,short-chain substituted or non-substituted alcohols such as ethanol,isopropanol, or propanol) can be added to the Base Composition. The BaseComposition is blended at medium speed for 24 hours at room temperaturein a glass roll bottle.

Optionally, a synthetic and semi-synthetic bioadhesive polymers such ashydroxyethylcellulose, polyvinylalcohol, polyacrylic acid, sodiumcarboxymethylcellulose, polyvinylpyrrolidone, or hydroxypropylcellulose(such as KLUCEL® LF) and a permeabilizing agents such as bile salts,surfactants, fatty acids and derivatives, chelators, malodextrins,cyclodextrins, or chitosan can be added to the blended Base Composition.If this step is taken, the Base Composition is then blended again atmedium speed for 24 hours at room temperature in a glass roll bottle.

The Final Formulation is prepared by dissolving a stabilizer (e.g.,antioxidants such as citric acid, or ascorbic acid) in a non-aqueoussolvent such as anhydrous ethanol in a low humidity environment. To thissolution add a dopamine agonist. The dopamine solution is added to theBase Composition to create a gel to be used for film casting.Optionally, a bioadhesive/active agonist release matrix such ashydroxypropylmethylcellulose or a non-aqueous solvent (e.g., propyleneglycol, glycerol, short-chain substituted or non-substituted alcoholssuch as ethanol, isopropanol, or propanol) can be added to the FinalFormulation.

The film is made by casting the Final Formulation on a film releaseliner fixed to a solid surface such as a glass plate. The film isallowed to dry until tacky and well formed while maintaining a surfacetemperature of about 60-70° C.

Film Dosage Form

According to one embodiment, a film dosage form comprises one or moreactive agents, about 0.5-10% film forming agent, about 5-20% stabilizingagent, about 10-95% bioadhesion enhancer, and up to about 50% solubilityenhancer.

According to a another embodiment, a film dosage form comprises one ormore active agents, about 1-6% film forming agent, about 5-10%stabilizing agent, about 50-85% bioadhesion enhancer, and about 0.5-20%solubility enhancer.

In another embodiment, a film dosage form comprises one or more activeagents, about 1-5% film forming agent, about 5-10% stabilizing enhancer,about 50-70% bioadhesion enhancer, and about 15-20% solubility enhancer.

In a further embodiment, a film dosage form comprises one or more activeagents, about 0.5-10% film forming agent, about 2-20% stabilizingenhancer, about 10-65% bioadhesion enhancer, and about 3.8-45%solubility enhancer with or without about 1-5% oleic acid.

In a further embodiment, a film dosage form comprises about 2-20% activeagents, about 0.5-10% film forming agent, about 2-20% stabilizingenhancer, about 20-95% bioadhesion enhancer, and about 3.8-45%solubility enhancer with or without about 1-5% oleic acid.

For the aforementioned gel dosage forms: the preferred film formingagent is Kollidon VA64; the preferred stabilizing agent is citric acid;the preferred bioadhesion enhancers are Kollidon 90F, FLUCEL, andhydroxypropylmethylcellulose; and the preferred solubility enhancers arePEG400, glycerol, and cyclodextrin.

For the aforementioned film dosage forms: the more preferred filmforming agent is Kollidon VA64; the more preferred stabilizing agent iscitric acid; the more preferred bioadhesion enhancers are Kollidon 90Fand FLUCEL; and the more preferred solubility enhancers are PEG400,glycerol, and cyclodextrin.

According to a preferred embodiment, a film dosage form comprises about2-20% dopamine agonist, about 10-55% Kollidon 90F, about 0.5-10%Kollidon VA64, about 0.3-5% PEG400, about 10-55% KLUCEL, about 0.5-10%glycerol, about 2-20% citric acid, and about 3-30% cyclodextrin with orwithout about 1-5% oleic acid.

Subcutaneous Dosage Form

The active agent is passed through a 40 mesh sieve and suspended in anemulsifying agent. To this solution a mediums or matrices (e.g.,synthetic, semi-synthetic or natural oils which can preferably beemployed are medium chain length triglycerides with a chain length offrom C₈ to C₁₀ in the carboxylic acid moiety, soybean oil, sesame oil,peanut oil, olive oil, coconut oil, castor oil, sunflower oil, saffloweroil or the corresponding hydrogenated oils or mixtures of at least twoof the aforementioned oils, bentonite, ethoxylated isostearyl alcohols,polyoxyethylene sorbitol and sorbitan esters, microcrystalline celluloseor derivatives thereof, plant gums, polyetheleneglycols of various size,aluminum metahydroxide, agar-agar and tragacanth, gelatins, or mixturesof two or more of these substances) is added. A resulting translucenthomogeneous emulsion of active agent can be used for parenteralapplication once passed through a sterilizing filter. It is recommendedto shake it well immediately before administration.

Subcutaneous Dosage Form

According to one embodiment, a subcutaneous dosage form comprises one ormore active agents, about 5-20% emulsifying agent and about 80-95%pharmaceutical medium.

In a further embodiment, a subcutaneous dosage form comprises one ormore active agents, about 5-10% emulsifying agent and about 90-95%pharmaceutical medium.

For the aforementioned subcutaneous dosage forms: the more preferredemulsifying agent is polysorbate 80 and the more preferred medium issesame seed oil.

In a further embodiment, a subcutaneous dosage form comprises one ormore active agents, about 0.01-0.1 bromocritpine, about 5-10%polysorbate 80, and about 90-95% sesame seed oil.

The examples listed below demonstrate that manipulations to thecomponents of parenteral dopamine agonist formulations can be made thatproduce predictable changes in the profile of the peak-plateaubioavailability curve and when administered parenterally exhibit thedesired peak-plateau bioavailability curves in vivo. Appropriately timeddaily parenteral administration of dopamine agonist formulations, whichexhibit the desired peak-plateau bioavailability curve, reduce metabolicdisorders in well established animal models of metabolic disease (seeExamples 18-21 and FIGS. 3-8). Furthermore, these parenteralformulations of dopamine agonists can be made to be stable to heat andhumidity under standard sample bottling conditions (see Example 22).

Several excipients may have an effect on the dissolution profile of theactive agent. For example, as the excipients of ProSolv (microcellulosefiller) and Benecel® (bioadhesive/active agonist release matrix;hydroxypropylmethylcellulose) increase in concentration, they act toslow the dissolution rate of the active agent. Contrariwise, theexcipients of citric acid and Pharmaburst accelerate the early andoverall dissolution rate of the dopamine agonist, respectively. Whenadditional citric acid is added and the Benecel® levels are reduced, theoverall dissolution rate of the dopamine agonist maintains the desiredearly fast dissolution profile followed by a slower constantdissolution. If the citric acid level is further increased (as seen withformulation 11S tablet described below), then surprisingly, the earlyburst-release of the formulation is markedly enhanced with about 40%released within the first 30 minutes followed by a slower but constantrelease for the next 210 minutes. Cyclodextrin can be added to improvethis release profile while enhancing the absorption characteristics ofthe formulation, as seen in formulation 12S below.

If one switches the Explotab (sodium starch glycolate and sodiumcarboxymethyl starch) disintegrant for Pharmaburst, the disintegrationtime is also accelerated (from about 15 to 5 minutes). This accelerateddisintegration is a desirable characteristic for parenteral tabletadministration. Also, use of Pharmaburst accelerates the overalldissolution profile of the formulation. Moreover, it can be appreciatedthat by altering the ratio of Explotab versus Pharmaburst as well asadjusting the Benecel® and ProSolv levels in the tablet, an intermediaterelease profile of dopamine agonist can be achieved. Such hybridformulations allow for “fine-tuning” of the desired formulation ofdopamine agonist to produce the desired PK profile. Adding Efffersoda toPharmaburst further accelerates the disintegration and dissolution timesof the dopamine agonist formulation.

Further Bioadhesive levels can be adjusted in these parenteralformulations to a maximum level of bioadhesive to support thebioadhesion of the active agent while still allowing for a quick burstdissolution of active agent. Increasing the level of bioadhesive resultsin a slowing of active agent dissolution time, however, reducingbioadhesive levels has no effect on dissolution time. Therefore, therelative amounts of bioadhesive agent, active agent, and othercomponents can be optimized to produce the desired peak-plateaubioavailability profile. It can further be demonstrated that increasingthe active agent from 1 to 3 mg per tablet does not alter thedissolution characteristics of the tablet so a range of dosage strengthsof parenteral dopamine agonists can be made. Although, upon increasingthe active agent level from 1 to 3 mg per tablet in a formulation thatcontains a cyclodextrin or other permeabilizing agent in conjunctionwith bioadhesive, it is possible to accelerate the release of activeagent by increasing its level relative to the cyclodextrin/bioadhesivelevel. Within this context, the release profile of the active agentwithin the tablet can be slowed by switching to a more potentbioadhesive, such as xanthan gum.

EXAMPLES Procedures

Tablets may be tested for hardness using a Hardness Tester (Model # PAH01, 500N, Pharma Alliance Group). The force at break point was recordedas the hardness of the tablet, or the crushing strength of the tablet.The values over 4 kg were generally considered acceptable.

Friability testing may be carried out following the USP <1216> guidelineusing the Key FT-400 model Friability Tester. A minimum of five tabletsfrom are weighed and placed in the tumbler. Tablets are rotated at 25RPM for approximately 4 minutes (100 rotations). The acceptablequalification corresponded to the USP acceptance criteria requiringweight loss of not more than 1% of the total weight.

Disintegration tests may be carried out following the USP <701>guideline at 37° C. using a VanKel Disintegration Tester, Model10-91171B operating at 30 rpm and Lauda M6 Circulating Bath. Tablets areplaced in the observation cylinder and the basket assembly is attachedto the test apparatus. De-ionized water is used as the immersion fluid.

Dissolution tests may be carried out following the USP <711> guidelineusing a Distek 2100B Dissolution System at 37° C. For each formulation,13 tablets are tested for dissolution in a total of 450 mL of theimmersion media. For HPLC analysis, 100 μl aliquots are used for eachobservation time point. The concentration of drug was determined withthe aid of a calibration curve by quantitation of the API's HPLC peakarea. Because of the NAT's finding regarding the instability of the APIin phosphate buffers (pH 6.8), which are standards for the dissolutionstudies mimicking saliva environments. Preferably, dissolution is testedin citric acid buffer, pH 6.0.

HPLC

Typically, all the samples were analyzed immediately afterpreparation/collection to reduce decomposition of the API. The reversephase HPLC analysis was carried out using the following conditions:

Set-up: WISP 712 Automatic Injection System (Waters) with WISP SamplesCooling Unit equipped with Waters 484MS Tunable Absorbance Detector andWaters 600E Multisolvent Delivery System; Eppendorf CH-30 ColumnHeater/TC-50 Controller; and Shodex Solvent Degassing Unit Model KT-375.

HPLC Column: Waters Symmetry Shield RP-18, 4.6×150 mm, 3.5 μM.

Detection wavelength: 300 nm.

Analytical Method: Phase A Water, 95%/Acetonitrile 5%, 0.1% TFA; Phase BAcetonitrile, 0.1% TFA; 20-35% gradient of B over 5 min, followed by35-40% gradient of B over 15 min. API's retention time was ca. 12.3 min.

Calibration Curve: the API's solution in 0.1% citric acid.

Example 1 Acrylic-Based Formulations

The solid parenteral dosage forms 1S-3S were prepared to include:

Formulation

1S 1S 2S 2S 3S 3S Excipient Type/Function Amt % mg Amt % mg Amt % mgBromocriptine API 1.43 320.0 1.43 320.0 1.43 120.0 Citric Acid,Solubility 9.99 2240.0 n/a n/a n/a n/a Anhydrous EnhancerCab-o-Sil/Cabot Fumed 0.40 89.6 0.40 89.6 0.40 33.6 M-5P, Silica/FillerCarbopol ® Bioadhesive/ 9.99 2240.0 9.99 2240.0 20.00 1680.0 974/NoveonRelease Matrix Mg Stearate Glidant 1.00 224.0 1.00 224.0 1.00 84.0Granular Mannitol Filler 77.20 17312.0 77.20 19552.0 17.17 6282.4 Total100.00 22425.6 100.00 22425.6 100.00 8200.0 n/a: not addedA 50 mL tube blender was charged with bromocriptine and Cab-o-Sil. Themixture was agitated at 300 rev/min for 10 minutes. In the case of 1S,citric acid was added and blended for 15 minutes. Carbopol was added andblended for 15 minutes followed by the addition of mannitol and furtherblending for 30 minutes. The mixture and Mg stearate was pushedseparately through a 40 mesh sieve and then mixed together for 2minutes. The dry granulation mixture was pressed into uniform tablets (5mm die, 70-75 mg) using the TDP press at 4,000 Psi.

Results

Tablet Characteristics 1S 2S 3S Hardness 5.94 kg 6.86 kg Good (Not exp.Tested) Friability Pass Pass Pass Disintegration Time 30 min 30 min 60min Flowability Good Moderate Poor Tablet Uniformity Poor-Fair Poor-FairPoor-Fair

Dissolution Profile 1S 2S 3S % Cumulative % Cumulative % Cumulative T,min Release Release Release 0 0.00 0.00 0.00 30 10.47 21.70 11.92 6021.47 37.62 16.28 90 10.96 12.63 20.91 150 n/t n/t 23.05 180 n/t n/t29.22 210 n/t n/t 24.77 n/t: not tested

Examples 2 Hydroxypropyl Methylcellulose/Polyvinyl Pyrrolidone-BasedSolid Formulations

Hydroxypropyl methylcellulose/Polyvinyl pyrrolidone-based solidformulations dosage forms (4S, 5S) were prepared as follows:

Formulation

4S 5S Excipient Type/Function Amount % mg Amount % mg Bromocriptine API1.43 220.00 1.43 220.00 Cab-o-Sil/Cabot Fumed Silica/Filler 0.41 62.70n/a n/a M-5P, Polyvinyl Bioadhesion Enhancer 7.14 1100.00 7.14 1100.00Pyrrolidone (PVP) Benecel ® MP814 Hydroxypropylmethylcellulose/ 35.725500.00 35.71 5500.00 Bioadhesive/API Release Matrix Mg Stearate Glidant1.00 154.00 1.00 154.00 Spray Dried Filler 54.30 8360.00 54.71 8426.00Mannitol Total 100.00 15396.70 100.00 15400.00 n/a: not addedA 50 mL tube blender was charged with bromocriptine and optionallyCab-o-Sil (4S). The mixture was agitated at 300 rev/min for 10 minutes.IPVP was added and blended for 15 min followed by the addition ofBenecel® and further blending for 20 minutes. Next, mannitol was addedand the mixture was blended for 30 minutes. The mixture and Mg stearatewere pushed separately through a 40 mesh sieve and then mixed togetherfor 2 minutes. The dry granulation mixture was pressed into uniformtablets (5 mm die, 70-75 mg) using the TDP press at 4,000 Psi.

Example 3 Citric Acid Buffer in the Dissolution Test

The use of citric acid buffer rather than a phosphate buffer was used totest the dissolution rate of formulation 6S. The formulation 6S released50% of the bromocriptine within the first two hours followed by adecrease in the bromocriptine concentration. The decrease inconcentration was not due to degradation of the bromocriptine.

Formulation

Formulation 6S Excipient Type/Function Amount, % mg Bromocriptine API1.43 220.00 Polyvinyl Pyrrolidone Bioadhesion 5.71 880.00 (PVP) EnhancerBenecel ® MP814 Hydroxypropyl- 10.43 1606.00 methylcellulose/Bioadhesive/ API Release Matrix Mg Stearate Glidant 1.00 154.00 SprayDried Mannitol Filler 61.43 9460.00 Cab-o-Sil/Cabot Fumed Silica/Filler10.0 1540 Total 100.00 15400.00A 50 mL tube blender was charged with bromocriptine and PVP. The mixturewas agitated at 300 rev/min for 10 min. Cab-o-sil was added and blendedfor 15 min followed by the addition of Benecel® with further blendingfor 20 min. Next, mannitol was added and the mixture was blended for 30min. The mixture and Mg stearate were pushed separately through a 40mesh sieve and then mixed together for 2 min. The dry granulationmixture was pressed into uniform tablets (5 mm die, 70-75 mg) using theTDP press at 4,000 Psi.

Results

Tablet Characteristics 6S Hardness 5.02 kg Friability PassDisintegration Time 30 min Flowability Poor Tablet Uniformity GoodDissolution: Immersion Media: Citric Acid Buffer, pH 6.0 (See tablebelow for dissolution profile)

Dissolution Profile of 6S % Cumulative T, min Release 0 0.00 60 34.94120 47.28 180 38.10 240 32.63 300 72.45

Examples 4 Additional HPMC/PVP-Based Formulations

Solid parenteral dosage forms (7S-10S) of the present invention wereprepared. The formulation 7S displayed good stability within the courseof the experiments. It released 50% of the drug after 4 hours and 70% ofthe drug after 6 h, with an excellent overall release profile. Also,this formulation allowed the manufacture of high quality tablets thathad respectable flow properties and uniformity, and low friability.Based on 7S, further experiments explored other strategies to slightlyspeed up the release of the API and bring it up to the target valueof >80% at 4 h. However, increasing levels of the microcrystallinecellulose reduced the release time and could be used to slow the releaseof buccal formulations of dopamine agonists. In the next iterativeround, formulations 9S and 10S were enhanced by citric acid andcontained stearic acid as glidant instead of Mg stearate (to reducedecomposition). As compared to 7S, 9S had 1.4% citric acid resulting inaccelerated release of the API, 86% at 3 h and 100% at 4 h. 10Scontained less HPMC than 7S and released 70% of API at 3 h and 95% at 4h. Both 9S and 10S had good stability, made excellent tablets, anddisplayed reduced disintegration time, in the range of 13-15 min.

Formulations

7S 8S 9S 10S Excipient Amt % mg Amt % mg Amt % mg Amt % mg Bromocriptine1.43 220.0 1.43 220.0 1.43 220.0 1.43 220.0 Polyvinyl Pyrrolidone 5.71880.0 5.71 880.0 5.71 880.0 5.71 880.0 (PVP) Benecel ® MP814 14.712266.0 14.71 2266.0 7.36 1133.0 7.36 1133.0 Explotab 10.00 1540.0 10.001540.0 10.00 1540.0 10.00 1540.0 ProSolv SMCC 10.00 1540.0 33.57 5170.010.01 1540.0 10.01 1540.0 Mg Stearate 1.00 154.0 1.00 154.0 n/a n/a n/an/a Steric Acid n/a n/a n/a n/a 1.00 154.0 1.00 154.0 Spray DriedMannitol 61.43 9460.0 33.57 5170.0 1.43 220.0 64.47 9922.0 Citric Acid,n/a n/a n/a n/a 63.05 9702.0 n/a n/a Anhydrose Total 100.00 15400 100.0015400 100.00 15389 100.00 15389 n/a: not addedA 50 mL tube blender was charged with bromocriptine and polyvinylpyrrolidone (PVP) and optionally citric acid (9S). The mixture wasagitated at 300 rev/min for 10 min. Explotab was added and blended for10 min followed by addition of the ProSolv together with Benecel® and 15min of blending. Next, mannitol was added and blended for 30 min. Themixture and separately Mg stearate was pushed through a 40 mesh sieveand then mixed together for 2 min. The dry granulation mixture waspressed into uniform tablets (5 mm die, 70-75 mg) using the TDP press at4,000 Psi.

Results

Tablet Characteristics 7S 8S 9S 10S Hardness 5.02 kg n/t 9.34 kg 11.46kg Friability Pass Pass Pass Pass Disintegration Time 95 min 95 min12-13 min 12-13 min Flowability Good Good Excellent Excellent TabletUniformity Good Good Good Good

Dissolution Immersion Media Citric Acid Buffer, pH 6.0

Dissolution Profile 7S 8S 9S 10S % % % % Cumulative CumulativeCumulative Cumulative T, min Release Release Release Release 0 0.00 0.000.00 0.00 30 19.17 8.68 22.72 19.49 60 23.12 15.81 32.12 27.59 90 28.00n/t n/t n/t 120 30.64 22.13 61.20 45.62 180 39.51 n/t 86.00 69.73 222n/t 32.97 n/t n/t 240 48.27 n/t 101.33 95.31 267 n/t 36.76 n/t n/t 30059.40 39.38 101.46 100.30 360 71.86 44.76 n/t n/t n/t: not tested

Examples 5 Burst-Release Formulations

In the next round of experiments a formulation 11S was prepared withelevated level of citric acid and a formulation 12S was complemented bya permeation enhancer (a cyclodextrin). The formulation 11S (elevatedcitric acid, 2.9% vs. 9S) was found to display “release burst” features.This effect of increasing the citric acid level to this amount is anunexpected result and one that has not been previously described fordopamine agonist formulations.

Formulations 11S and 12S were prepared to include: (1) the dopamineagonist, bromocriptine mesylate; (2) hydroxypropyl methylcellulose(HPMC); (3) polyvinyl pyrrolidone (PVP); (3) elevated levels of citricacid; and (4) optionally, a permeation enhancer (12S). The formulation11S (2.9% citric acid than 9S) was found to display a “release burst”compared to previous formulations. The total release time was still verysimilar to 9S, (˜4 h), however, a greater amount of 11S was released atearlier time points (as much as 36% was released within 30 min and then46% released by 60 min). A high level of citric acid was employed forthe next formulation, 12S with a permeation enhancer from thecyclodextrin family. The 12S formulation (2.5% citric acid and with 14%cyclodextrin compared to 9S) displayed an even more pronounced effect ofthe “release burst” behavior. Specifically, 40% of bromocriptine wasreleased at 30 min, followed by a slower rate of release (52% at 1 h,71% at 2 h, 91% at 3 h, and finally full release observed by the 4 htime point).

Formulations

11S 12S Excipient Type/Function Amount % mg Amount % mg BromocriptineAPI 1.43 250.00 1.43 250.00 Polyvinyl Bioadhesion Enhancer 5.71 1000.005.71 1000.00 Pyrrolidone (PVP) Benecel ® MP814 HydroxypropylMethylcellulose/ 7.36 1287.50 7.36 1287.50 Bioadhesive/API ReleaseMatrix Explotab Modified Starch/Disintegrant 10.00 1750.00 10.00 1750.00ProSolv Microcrystalline Cellulose/Filler 10.01 1750.00 10.0 1750.00Citric Acid, Solubility, Stability 2.86 500.00 2.86 500.00 AnhydrousStearic Acid Glidant 1.00 175.00 1.00 1750.00 Spray Dried Filler 61.629922.00 47.32 8275.00 Mannitol Cavitron 82001 HydroxtpropylCyclodextrin/ n/a n/a 14.30 2500.00 Permeation Enhancer Total 100.0017487.00 100.00 15400.00 n/a: not addedA 50 mL tube blender was charged with bromocriptine, citric acid andpolyvinyl pyrrolidone (PVP). The mixture was agitated at 300 rev/min for10 min. Benecel® was added and blended for 10 min. Next, Explotab wasadded and blended for 10 min followed by addition of the ProSolv (1750mg) and 15 min of blending. In the case of formulation 12S, Cavitron wasdispersed using the ball mill, added, and blended for 20 min. Next,mannitol was added and blended for 30 min. The mixture and separately Mgstearate was pushed through a 40 mesh sieve and then mixed together for2 min. The dry granulation mixture was pressed into uniform tablets (5mm die, 70-75 mg) using the TDP press at 4,000 Psi.

Results

Tablet Characteristics 11S 12S Hardness 8.33 kg 10.49 kg Friability PassPass Disintegration Time 10-11 min 14-15 min Flowability ExcellentPassable but needs improvement Tablet Uniformity Good Good

Dissolution Immersion Media Citric Acid Buffer, pH 6.0

Dissolution Profile 11S 12S % Cumulative % Cumulative T, min ReleaseRelease 0 0.00 0.00 30 36.51 40.37 60 46.60 52.65 120 64.51 70.87 18081.26 91.58 240 97.91 100.35

Example 6 Combination Tablet of Dopamine Agonist Plus aCholesterol-Lowering Agent

The cholesterol-lowering agent simvastatin was added to formulation 11Sto create formulation 20S. It was found that the 11S formulation wasable to incorporate an additional agent from the statin family withoutappreciably altering the release profile of the dopamine agonist.

The addition of the simvastatin to the mixture greatly reduced flowproperties due to the fact that simvastatin is a fluffy powder able topick up a static charge. Simvastatin also has a very poor solubility inwater. In the dissolution test, the measurable concentration ofsimvastatin only reached roughly 6% which was more than likely due toits poor solubility in water. This can be overcome by the addition oflipophilic solubilizing agents. More importantly, simvastatin did notappreciably alter the release profile of bromocriptine.

Formulation 20S

Formulation 20S Excipient/Manufacturer Type/Function Amount % mgBromocriptine API 1.43 250.00 Simvastatin API 7.15 1250.00 PolyvinylPyrrolidone Bioadhesion Enhancer 5.71 1000.00 (PVP) Benecel ® MP814Hydroxypropyl 7.36 1287.50 Methylcellulose/ Bioadhesive/API ReleaseMatrix Explotab Modified Starch/ 10.00 1750.00 Disintegrant ProSolvSMCC/JRC Microcrystalline 10.01 1750.00 Cellulose/Filler Citric Acid,Anhydrous Solubility, Stability 2.86 500.00 Stearic Acid Glidant 1.00175.00 Spray Dried Mannitol Filler 61.62 9525.00 Total 100.00 17487.00The formula preparation was the same as for 11S, with the additionalstep following the 300 rev/min of blending simvastatin into the mixturefor 10 minutes.

Results

Tablet Characteristics 20S Hardness 9.0-10.0 kg Friability PassDisintegration Time 14.5-16 min Flowability Poor Tablet Uniformity Notdetermined

Dissolution Immersion Media: Citric Acid Buffer, pH 6.0

Dissolution Rate of Bromocriptine % Cumulative T, min Release 0 0.00 3019.04 60 43.78 120 72.64 180 88.94 240 105.46 300 110.28

Dissolution Rate of Simvastatin % Cumulative T, min Release 0 0.00 306.46 60 5.83 120 6.84 180 5.61 240 6.15 300 6.46

Example 7 Combination Tablet of Dopamine Agonist Plus Anti-HypertensiveAgent or Cholesterol-Lowering Agent

The anti-hypertensive agent ramipril was added to the formulation of 11Sto create formulation 21S. It was found that the 11S formulation wasable to incorporate an additional agent from the angiotensin convertingenzyme inhibitor family without appreciably altering the release profileof the dopamine agonist.

Formulation 21S

Formulation 21S Excipient/Manufacturer Type/Function Amount, % mgBromocriptine API 1.43 250.00 Ramipril API 7.15 1250.00 PolyvinylPyrrolidone (PVP) Bioadhesion Enhancer 5.71 1000.00 Benecel ® MP814Hydroxypropyl Methylcellulose/ 7.36 1287.50 Bioadhesive/API ReleaseMatrix Explotab Modified Starch/Disintegrant 10.00 1750.00 ProSolvSMCC/JRC Microcrystalline Cellulose/Filler 10.01 1750.00 Citric Acid,Anhydrous Solubility, Stability 2.86 500.00 Stearic Acid Glidant 1.00175.00 Spray Dried Mannitol Filler 61.62 9525.00 Total 100.00 17487.00The formula preparation was the same as for 11S, with the additionalstep following the 300 rev/min of blending ramipril into the mixture for10 minutes.

Results

Tablet Characteristics 21S Hardness 9.5-9.8 kg Friability PassDisintegration Time 10.5-11.5 min Flowability Very Poor TabletUniformity Not determined

Dissolution Immersion Media Citric Acid Buffer, pH 6.0

Dissolution Profile of Bromocriptine % Cumulative T, min Release 0 0.0030 32.23 60 51.73 120 51.37 180 6.82 240 89.15 300 98.09

Dissolution Profile of Ramipril % Cumulative T, min Release 0 0.00 3012.47 60 16.83 120 21.16 180 26.16 240 33.23 300 34.92

Example 8 Combination Tablet of Dopamine D2 Receptor Agonist PlusDopamine D₁ Receptor Agonist

Formulation 22S was a combination of a dopamine D₁ receptor agonist,bromocriptine, and a dopamine D2 receptor agonist, SKF-38393, employingthe 11S base formulation with the two active agents. The releaseprofiles for each dopamine agonist were remarkably similar and exhibiteddissolution profiles very similar to the 11S formulation. A short studyhas been run to ensure the stability of SKF-38393. We found that nodecomposition takes place in water buffered by the acidic acid within 12h. In contrast, in alcohol solution, the API decomposes rapidly,with >5% of the API already lost within the first hour. Despite thelarge amount of SKF-38393, the formulation displayed good flowproperties and produced quality tablets.

Formulation 22S

Formulation 22S Excipient/ Amount Manufacturer Type/Function % mgBromocriptine API 1.43 125.00 SKF-38393 API 14.86 1250.00 PolyvinylBioadhesion Enhancer 5.71 500 Pyrrolidone (PVP) Benecel ® MP814Hydroxypropyl Methylcellulose/ 7.36 650 Bioadhesive/API Release MatrixExplotab Modified Starch/Disintegrant 10.00 875.00 ProSolv SMCC/JRCMicrocrystalline Cellulose/Filler 10.01 875.00 Citric Acid, Solubility,Stability 2.86 250 Anhydrous Stearic Acid Glidant 1.00 87.5 Spray DriedFiller 47.29 4137.5 Mannitol Total 100.00 8750.00The formula preparation was the same as for 11S, with the additionalstep following the 300 rev/min of blending SKF-38393 into the mixturefor 10 minutes.

Results

Tablet Characteristics 22S Hardness 10.2-10.6 kg Friability PassDisintegration Time 12.5 min Flowability Good Tablet Uniformity Notdetermined

Dissolution Immersion Media Citric Acid Buffer, pH 6.0

Dissolution Profile of Bromocriptine-22S % Cumulative T, min Release 00.00 30 19.04 60 43.78 120 72.64 180 88.94 240 105.46 300 110.28

Dissolution Profile of SKF-38393-22S % Cumulative T, min Release 0 0.0030 44.46 60 62.22 120 85.08 180 102.21 240 108.80 300 110.58

Example 9 Accelerated Burst-Release Formulations

Based on the Results of the 11S and 12S formulations, the next series offormulations (23S, 24S) were created to further accelerate both thetablet disintegration time and the dissolution time for the dopamineagonist preparation. This was effectively accomplished by replacing theExplotab® disintegrant with a Pharmaburst® disintegrant, which reducedthe disintegration time from 13-15 minutes to about 5 minutes andaccelerated the dissolution time for 100% dissolution from about 4 hoursto about 1.0-2.0 hours. Formulations 23S and 24S displayed excellentflow properties and generated very robust hard tablets with fastdisintegration time with 24S disintegrating a bit faster than 23S. Thesefindings as consistent with our previous observations that Cavitronslows down disintegration time (e.g., 11S vs. 12S).

Formulations

23S 24S Excipient Type/Function Amount % mg Amount % mg BromocriptineAPI 1.43 250.00 1.43 250.00 Polyvinyl Bioadhesion Enhancer 5.71 1000.005.71 1000.00 Pyrrolidone (PVP) Benecel ® MP814 HydroxypropylMethylcellulose/ 7.36 1300.00 7.36 1300.00 Bioadhesive/API ReleaseMatrix Citric Acid, Solubility, Stability 2.86 500.00 2.86 500.00Anhydrous Stearic Acid Glidant 1.00 175.00 1.00 175.00 PharmaburstDisintegrant, Filler 81.64 14275.00 81.64 11785.00 Cavitron 82004Hydroxypropyl n/a n/a 14.30 2500.00 Cyclodextrin/Permeation EnhancerTotal 100.00 17500.00 100.00 15400.00 n/a: not addedA 50 mL tube blender was charged with bromocriptine, citric acid andpolyvinyl pyrrolidone (PVP). The mixture was agitated at 300 rev/min for10 min. Benecel® was added and blended for 10 min. In the case offormulation 24S, Caviton was added and blended for 10 min. Next,Pharmaburst was added and blended for 30 min. The mixture and separatelyMg stearate was pushed through a 40 mesh sieve and then mixed togetherfor 2 min. The dry granulation mixture was pressed into uniform tablets(5 mm die, 70-75 mg) using the TDP press at 4,000 Psi.

Results

Tablet Characteristics 23S 24S Hardness 12.9 kg 13.4 kg Friability PassPass Disintegration Time 5 min 7.5 min Flowability Excellent ExcellentTablet Uniformity Good Good

Dissolution Immersion Media Citric Acid Buffer, pH 6.0

Dissolution Profile 23S 24S % % Cumulative Cumulative T, min ReleaseRelease 0 0.00 0.00 30 80.84 34.38 60 102.37 60.28 120 105.67 106.87 180105.17 114.67 240 105.92 116.05 300 n/t 116.05 n/t: not tested

Example 10 Dual Layer Tablets for Peak-Plateau Dissolution Profiles ofDopamine Agonists

Dual layer tablets 30DL were designed to produce a release profileintermediate between 23S and 24S. The tablets were produced using Carverpress and displayed the expected release characteristics. Thisexperiment confirms the possibility of using dual layer tablets for finetuning of other formulations to achieve (and modify by accelerating thetime to peak or slowing the tail plateau times) desired peak-plateaudopamine agonist release profiles.

The tablets (70 mg) were punched one by one into a 5 mm die on abench-top 20 Ton Carver press using pre-weighted amounts of the twocomponents, A and B (35 mg each) at 2000 Psi pressure. Before applying apress force, the formulation mixture was pre-compressed in a two-stepprocess using manual power. Each tablet was examined for visibleirregularities and the quality of the interface layer aided by adding ayellow dye to the component A.

Formulation of Components A and B

30DL A 30DL B Excipient Type/Function Amount % mg Amount % mgBromocriptine API 1.43 250.00 1.43 250.00 Polyvinyl Bioadhesion Enhancer5.71 1000.00 5.71 1000.00 Pyrrolidone (PVP) Benecel ® MP814Bioadhesive/API Release Matrix 7.36 1300.00 7.36 1300.00 Citric Acid,Solubility, Stability 2.86 500.00 2.86 500.00 Anhydrous Stearic AcidGlidant 1.00 175.00 1.00 175.00 Pharmaburst Disintegrant, Filler 81.1614191.00 81.16 11785.00 Al Lake Pigment Dye 0.48 84 n/a n/a No. 10Cavitron 82004 Hydroxypropyl n/a n/a 14.3 2500.00Cyclodextrin/Permeation Enhancer Total 100.00 17500.00 100.00 17500.00n/a: not addedA 50 mL tube blender was charged with 250 mg of bromocriptine, citricacid, and polyvinyl pyrrolidone (PVP). The mixture was agitated at 300rev/min for 10 min. Benecel® and optionally Lake Pigment (A) were addedand blended for 10 min. In the case of component B, Cavitron (2500 mg)was added and blended for 10 min. Next, Pharmaburst was added andblended for 30 min. The mixture and separately Mg stearate was pushedthrough a 40 mesh sieve and then mixed together for 2 min.

Results

Tablet Characteristics 30DL Hardness n/t Friability Pass DisintegrationTime n/t Flowability n/t Tablet Uniformity Good n/t: not tested

Dissolution Immersion Media Citric Acid Buffer, pH 6.0

Dissolution Profile of Bromocriptine-30DL T, min % Cumulative Release 00.00 30 49.30 60 73.54 120 91.04 240 97.32 300 97.88

Example 11 Ergocriptine Incorporated into the 12S Formulation

For formulation 25S, the bromocriptine in formulation 12S was replacedby the dopamine agonist ergocriptine. The release profiles for eachdopamine agonist were remarkably similar and exhibited dissolutionprofiles very similar to the 12S formulation.

Formulation 25S

Formulation 25S Excipient/Manufacturer Type/Function Amount % mgErgocriptine API 1.43 250.00 Polyvinyl Pyrrolidone Bioadhesion Enhancer5.71 1000.00 (PVP) Benecel ® MP814 Hydroxypropyl 7.36 1287.50Methylcellulose/ Bioadhesive/API Release Matrix Explotab ModifiedStarch/ 10.00 1750.00 Disintegrant ProSolv SMCC/JRC Microcrystalline10.01 1750.00 Cellulose/Filler Cavitron 82004 Hydroxypropyl 14.302500.00 Cyclodextrin/ Permeation Enhancer Citric Acid, AnhydrousSolubility, Stability 2.86 500.00 Stearic Acid Glidant 1.00 175.00 SprayDried Mannitol Filler 47.32 8275.00 Total 100.00 17487.00The formulation was prepared as described above for formulation 12S,with ergocriptine rather than bromocriptine.

Results

Tablet Characteristics 25S Hardness 10.7-10.9 kg Friability PassDisintegration Time 16-18 min Flowability Excellent Tablet UniformityGood

Dissolution Immersion Media: Citric Acid Buffer, pH 6.0

Dissolution Profile of Ergocriptine-25S % Cumulative T, min Release 00.00 30 39.12 60 53.53 120 71.12 240 94.09

Example 12 Gel Dopamine Agonist Formulations

A series of gel formulations (26S, 31Gel and 34Gel) were constructed toprovide for mucosal, transdermal, and/or subcutaneous administration ofdopamine agonists with good product stability (i.e., shelf life). Sinceacrylic based formulations degrade dopamine agonists, particularly thoseof the ergot-family, a different formulation not employing any acryliccomponents that still provided the acceptable peak and plateaupharmacokinetic profile was constructed.

The trans-dermal, transmucosal bromocriptine formulation 26S was basedon a non-aqueous glycerol-containing composition. Propylene glycol (PEG)provides high solubility of dopamine agonists such as bromocriptine andalso is a proven trans-dermal permeation enhancer compliant with FDA andcGMP guidelines. According the U.S. Pat. No. 4,366,145, bromocriptinecompositions containing high level of glycerol and propylene glycol havehigh stability. Additionally citric acid was introduced to increase thestability of API dopamine agonists. Finally, silica, an inorganicmaterial, was used for viscosity control, as it is unlikely to affectstability in contrast to the thickening agents based on acrylic acidderivatives, and even PEG which we have shown to accelerate degradationof ergot-related dopamine agonists.

For the bioadhesive system, a mixture of hydroxypropyl cellulose(Benecel®) and Crosspovidone in a 2:1 ratio was added to the tabletformulations. This bioadhesive combination is expected to generate a gelwith good API stability. A short-term stability study showed that nodecomposition took place within 72 h after storing the gel in therefrigerator at 4° C.

Gel formulation 31Gel was developed using formulation 26S based on thenon-aqueous system that included glycerol and propylene glycol with aviscosity controlled by addition of silica. After preliminaryexperimentation, a HPMC/PVP bioadhesive was added to this gelcombination. Aerosil silica allows for an effective control of stabilityproducing a gel that shows good homogeneity after one week of storage.Additionally, no decomposition of bromocriptine was been detected after3 days when stored at 5° C. As compared to the gel formulation 26S, lesssilica was required to achieve similar thickening effect due to theaddition of the bioadhesive component.

Gel formulation 34Gel was the same as 26S, however with 3% active agentinstead of 1% active agent.

These formulations were stable and do not include any acrylic basedingredients which are known to accelerate the degradation ofergot-related dopamine agonists. The viscosity and bioavailabilityproperties of these gels may be adjusted by methods that allow for themaintenance of the bioavailability profile and yet increase theabsorption level of the active agent from the formulation.

These preparations can be applied transdermally, subcutaneously, ortransmucosally to affect parenteral absorption.

Formulations

26S 31Gel 34Gel Excipient Type/Function Amt % g Amt % g Amt % gBromocriptine API 1 0.9 1.03 0.9 3 2.7 Propylene Glycol Solvent,Trans-dermal delivery USP 20 18.0 20.7 18.0 20 18.0 grade, SpectrumGlycerol Solvent, Trans-dermal delivery 68 61.2 62.2 54.15 66 59.4Silica 200 Degussa Thickener 10 9.0 6.9 6.0 10 9.0 Citric Acid Stabilitycontrol 1 0.9 1 0.9 1 0.9 Anhydrous Benecel ® MP814 Bioadhesive n/a n/a5.4 4.7 n/a n/a Polyvinyl Bioadhesive n/a n/a 2.7 2.35 n/a n/aPyrrolidone (PVP) Total 100.00 90.0 100.00 90.0 100.00 90.9 n/a: notaddedFor formulations 26S and 34Gel, in a 100 mL screw-cap bottle, citricacid was sonicated in propylene glycol for 10 min resulting in clearcolorless solution. Bromocriptine was added and sonicated for 10 minproducing slightly translucent liquid. Glycerol was added and themixture was sonicated for and additional 10 minutes. Silica wasgradually added to solution, with a help of manual stirring andsonication. In the initial periods after addition very viscousheterogeneous slurry was generated that gradually clears up.

In the case of 31Gel, Benecel® and Povidone 29/32 were added to theglycerol and the resulting suspension homogenized using a Polytronhomogenizer at 5, 000 rpm for 5 min. The resulting slurry was thenpushed though the size 40 stainless steel mesh sieve to ensure theabsence of the conglomerated particles. The milky creamy suspension (thestock solution slowly separated after several days of subsequent storagein the refrigerator) was added to the polypropylene mixture andsonicated for 5 min. 6 g of silica was gradually added to solution (2×3g), with a help of manual stirring and sonication. In the initialperiods after addition a very viscous heterogeneous slurry was generatedthat gradually cleared up. As compared to the gel formulation 26S, lesssilica was required to achieve similar thickening effect.

Because of the substantial amount of trapped air bubbles, after ageingthe gel formulations for 24 h at 5° C. in the refrigerator, the finalformulation was degassed in a vacuum desiccators for 6 h resulting in aclear slightly yellow gel. This final gel was packed into a round bottleequipped with an airless pump.

Example 13 Influence of Bioadhesive System Levels in the Tablet UponDissolution and Disintegration Profiles

In this example, the amounts of HPMC/PVP bioadhesives in formulation 23Swere altered. Formulation 27S contains a 20% higher load of HPMC/PVPbioadhesive system than 23S. As compared to 23S, 27S displayed asubstantially slowed release, with 60% of the drug released in 1 h and94% in 2 h. Using higher levels of bioadhesive components seems to be aninappropriate strategy for providing a quick peak of dopamine agonistfollowed by a slower tailed release.

Formulation 28F, on the other hand, has 50% less HPMC/PVP bioadhesivesas compared to formulation 23S. The release profile, however, was verysimilar to 23S. Taking into account the release data for 27S, theseresults indicated that the ratio of bioadhesive components selected for23S was near the inflection point of transition to a slow initialrelease of dopamine agonist at higher levels of bioadhesive (i.e., lossof initial rapid peak dissolution).

Formulation 27S

27S 28S Excipient Type/Function Amount % mg Amount % mg BromocriptineAPI 1.43 250.00 1.43 250.00 Polyvinyl Bioadhesion Enhancer 6.85 1200.002.86 500.00 Pyrrolidone (PVP) Benecel ® MP814 HydroxypropylMethylcellulose/ 8.83 1560.00 3.68 650.00 Bioadhesive/API Release MatrixCitric Acid, Solubility, Stability 2.86 500.00 2.86 500.00 AnhydrousStearic Acid Glidant 1.00 175.00 1.00 175.00 Pharmaburst Disintegrant,Filler 79.03 13815.00 88.18 15425.00 Total 100.00 17500.00 100.0017500.00

The formulations were prepared in the same manner as described for 23S.

Results

Tablet Characteristics 27S 28S Hardness 15.0-15.5 kg 15.0-15.5 kgFriability Pass Pass Disintegration Time 7.5-8.5 min 6 min FlowabilityGood Excellent Tablet Uniformity Good Good

Dissolution Immersion Media: Citric Acid Buffer, pH 6.0

Dissolution Profile 23S 27S 28S % % % Cumulative Cumulative CumulativeT, min Release Release Release 0 0.00 0.00 0.00 30 80.84 30.01 91.91 60102.37 60.28 93.10 120 105.67 93.92 96.32 180 105.17 n/t n/t 240 105.9298.15 96.92 300 n/t 101.07 97.37 n/t: not tested

Example 14 The Use of Xanthan Gum as the Bioadhesive System

Formulation 29S incorporated xanthan gum in place of HPMC, at the sameratio to other tablet components as in 23S, to investigate the influenceof such gums on tablet disintegration and dopamine agonist dissolutionprofiles. This change resulted in a significantly slower release of thedopamine agonist. Therefore, xanthan gum can only be considered as analternative to HPMC/PVP system at reduced levels, or in combination atreduced levels with a “super fast” disintegrating tablet (seeformulation 40SuF below) to effectuate the peak-plateau dissolutioncurve.

Formulation

Formulation 29S Amount, Excipient/Manufacturer Type/Function % mgBromocriptine API 1.43 250.00 Polyvinyl Pyrrolidone Bioadhesion Enhancer5.71 1000.00 (PVP) Xanthan Gum Bioadhesive/API 7.36 1300.00 ReleaseMatrix Citric Acid, Anhydrous Solubility, Stability 2.86 500.00 StearicAcid Glidant 1.00 175.00 Pharmaburst Disintegrant, Filler 81.64 14275.00Total 100.00 17500.00The formulation was prepared as described above for formulation 23S,with xanthan gum used as the bioadhesive rather than Benecel®.

Results

Tablet Characteristics 29S Hardness 14.0-14.5 kg Friability PassDisintegration Time 7.5-8.0 min Flowability Excellent Tablet UniformityGood

Dissolution Immersion Media: Citric Acid Buffer, pH 6.0

Dissolution of Bromocriptine-29S % Cumulative T, min Release 0 0.00 307.09 60 15.72 120 20.86 240 34.24 300 41.88

Example 15 Increase in Active Agent to Bioadhesive Ratio

The effect of increasing the dopamine agonist to bioadhesive ratio inthe tablet formulation was explored. Compositions 32F and 33S were madeas analogs of the 23S and 24S formulations, respectively, but withratios of dopamine agonist to bioadhesive system of approximately 2.5/10versus 1/10. As expected, the 32F formulation displayed a releaseprofile similar to 23S. Although the new composition 33S had 3 timesmore bromocriptine than 24S, it displayed a significantly differentrelease profile as compared to 24S. In fact, the release profile of 33Swas more similar to 23S than 24S, being that all of the drug wasreleased in about 120 min. The increase in active agent to bioadhesivesystem ration with the addition of cyclodextrin likely overloaded thedrug reservoir resulting in more drug being released initially. Thisformulation can be useful to deliver a fast load of drug followed by aslower release with the addition of a permeation enhancer such ascyclodextrin. One can adjust the rate of initial drug delivery with acyclodextrin-containing formulation by merely increasing the ratio ofdrug to cyclodextrin in the formulation so that its initial release wasnot a factor of its interaction with the cyclodextrin. By reducing thepercentage of drug interacting with the cyclodextrin, one can acceleratethe initial release of drug from the tablet.

Formulations

32F 33S Excipient Type/Function Amount % mg Amount % mg BromocriptineAPI 4.29 750.00 4.29 750.00 Polyvinyl Bioadhesion Enhancer 5.71 1000.005.71 1000.00 Pyrrolidone (PVP) Benecel ® MP814 HydroxypropylMethylcellulose/ 7.36 1300.00 7.36 1300.00 Bioadhesive/API ReleaseMatrix Citric Acid, Solubility, Stability 2.86 500.00 2.86 500.00Anhydrous Stearic Acid Glidant 1.00 175.00 1.00 175.00 PharmaburstDisintegrant, Filler 78.78 13775 64.48 11285.00 Cavitron 82004Hydroxypropyl n/a n/a 14.30 2500.00 Cyclodextrin/Permeation EnhancerTotal 100.00 17500.00 100.00 17500.00 n/a: not testedFormulations were preformed as described above for formulations 23S and24S.

Results

Tablet Characteristics 1S 2S Hardness 14.1-14.8 kg 8.1-9.1 kg FriabilityPass Pass Disintegration Time 8.0-8.5 min 12.0-12.5 min FlowabilityExcellent Excellent Tablet Uniformity Good Good

Dissolution Immersion Media: Citric Acid Buffer, pH 6.0

Dissolution Profile 32F 33S % Cumulative % Cumulative T, min ReleaseRelease 0 0.00 0.00 30 81.76 73.74 60 96.06 91.64 120 95.68 97.69 18098.16 99.50 240 97.95 100.52

Example 16 Replacement of Citric Acid with Ascorbic Acid in TabletFormulations

Formulation 35F was a 23S analog at 1 mg active agent per tablet andascorbic acid replaced for citric acid.

Formulation 36S was a 23S analog at 3 mg active agent per tablet andascorbic acid replaced for citric acid.

Formulation 37F was a 24S analog at 1 mg active agent per tablet andascorbic acid replaced for citric acid.

Formulation 38S was a 24S analog at 3 mg active agent per tablet andascorbic acid replaced for citric acid.

In all cases the replacement of citric acid with ascorbic acid resultedin a slower drug release and tablet disintegration time and can beemployed as a method to do so without reducing stability of the tablet.

Formulations

35F 36S 37F 38S Excipient Amt % mg Amt % mg Amt % mg Amt % mgBromocriptine 4.29 750.0 1.43 250.0 4.29 750.0 1.43 250.0 Polyvinyl 5.711000.0 5.71 1000.0 5.71 1000.0 5.71 1000.0 Pyrrolidone (PVP) Benecel ®MP814 7.36 1300.0 7.36 1300.0 7.36 1300.0 7.36 1300.0 Ascorbic Acid 2.86500.0 2.86 500.0 2.86 500.0 2.86 500.0 Stearic Acid 1.00 13775.0 1.00175.0 1.00 175.0 1.00 175.0 Pharmaburst 78.78 13815.0 81.57 14275 64.4811285 67.27 11775 Cavitron 82004 n/a n/a n/a n/a 14.3 2500.0 14.3 2500.0Total 100.00 17500 100.00 17500 100.00 17500 100.00 17500Dissolution of formulations were preformed as described above forformulations 23S and 24S.

Results

Tablet Characteristics 35F 36S 37F 38S Hardness 13.2-16.1 kg 13.7-15.4kg 14.5-15.6 kg 13.9-15.9 kg Friability Pass Pass Pass PassDisintegration Time 7.45-8.15 min 6.5-7.5 min 14.5-15.5 min 14.5-15.5min Flowability Moderate Good Very Poor Poor Tablet Uniformity GoodModerate Good Good

Dissolution Immersion Media: Citric Acid Buffer, pH 6.0

Dissolution Profile 35F 36S 37F 38S % % % % Cumulative CumulativeCumulative Cumulative T, min Release Release Release Release 0 0.00 0.000.00 0.00 30 46.68 53.60 30.19 19.84 60 73.43 81.69 47.22 26.99 12087.78 90.85 68.93 40.57 180 90.50 90.52 71.05 55.40 240 91.45 91.2869.35 70.71

Example 17 Very Rapid Disintegrating Tablets

A very rapid release tablet formulation (40SuF) was made utilizing aneffervescent-type disintegrant. In the formulation 40SuF, the level ofbioadhesive system was doubled (to roughly 25% total HPMC/PVP). Thisformulation resulted in rapidly disintegrating tablets (4 min) withhighly desirable “burst” release and almost linear subsequent “tailing”of slower release.

Formulation 40SuF

Formulation 40SuF Excipient/ Manufacturer Type/Function Amount % mgBromocriptine API 1.43 250.00 Polyvinyl Bioadhesion Enhancer 11.422000.00 Pyrrolidone (PVP) Benecel ® Bioadhesive/API Release Matrix 14.862600.0 MP814 Citric Acid, Solubility, Stability, Component 20.57 3600.0Anhydrous of the Effervescent Mixture Stearic Acid Glidant 1.00 175.00Effersoda-12 Effervescent Component 41.21 7225.0 PharmaburstDisintegrant, Filler 9.43 1650.0 Total 100.00 17500.00This formulation were prepared as described above for formulations 23Swith the addition of Efferesoda along at the time that citric acid wasadded.

Results

Tablet Characteristics 40SuF Hardness 6.7-7.6 kg Friability PassDisintegration Time 4.0 min Flowability Poor Tablet Uniformity Good

Dissolution Immersion Media Citric Acid Buffer, pH 6.0

Dissolution Profile of Bromocriptine 40SuF % Cumulative T, min Release 00.00 5 43.92 15 66.57 30 73.02 60 82.27 90 89.58

Example 18 In Vivo Bioavailability Studies with Solid ParenteralDopamine Agonist Formulations

Parenteral dosage forms of the present invention were administered toSyrian hamsters to demonstrate the in vivo bioavailability of thedopamine agonists. The large food storage pouch of the Syrian hamster isan ideal biological tissue to study mucosal transport of compounds anddrug formulations. The Syrian hamster also has a dermal tissue that canbe used to study transdermal transport of drug preparations. Dopamineagonist pharmaceutical preparations, of the present invention, wereadministered to anesthetized Syrian hamsters (n=2-9 per group). Bloodsamples were taken prior to and at 30, 60, 90, 120, 180, and optionallyat 240 and 300 minutes after drug administration, and the plasma levelof bromocriptine, the dopamine agonist in these formulations, wasmeasured. Bromocriptine was extracted from plasma and the samples wereanalyzed against standards via HPLC method. Bioavailability data arepresented as % of C_(max).

Plasma Bromocriptine Extraction Method

Two hundred and 50 microliters of plasma was mixed with 125 μl 0.5 MNHCl buffer (PH 9.2), and 900 ul hexane/1-butanol (5/1). The mixture wasvortexed (3 min) and centrifuged (1000×g, 3 min). The supernatant wastransferred to a set of new tubes, and 250 μl 0.025 M H₂SO₄. was thenadded to the tube. The mixture was vortexed (3 min) and centrifuged(1000×g, 3 min) again. After the top organic phase was aspirated, 500 μldichloromethane and 150 μl NDCl buffer was added and then vortexed andcentrifuged. The top aqueous layer was aspirate off and the bottom layerwas evaporated at 55° C. After dry, the residue was stored at −70° C.until analyzed by HPLC.

As demonstrated below, the parenteral dosage forms of the presentinvention produced peak-plateau bioavailability curves in the animalmodel system. Further, these bioavailability examples demonstrated thatit is possible to manipulate, in a predictive manner, the shape of thebioavailability curve by manipulating specific components of the drugformulation.

HPLC Analysis

The above extract was dissolved in 50 μl 50% Ethanol. 10 or 15 μl wasinjected into the HPLC for analysis.

Conditions:

Mobile phase: 0.1 M Dibasic potassium phosphate (pH 7.5): Acetonitrile(1:1).

Flow Rate: 0.4 ml/min.

Column: C₁₈ 3 ul, 100×2 mm.

Detector: UV at 300 nm.

Run Time: 2× the retention time of bromocriptine.

Bioavailability Data Analysis

Bioavailability is presented as % of C_(max). The data represent thebest-fit curve acquired per treatment group.

Bioavailability Results of Formulations 23S and 24S and the Combination30DL

The bioavailability of the 23S formulation was characterized by adopamine agonist peak plasma level within 30 minutes of drug mucosaladministration with a subsequent reduction in plasma levels shortlythereafter. When cyclodextrin was added to the 23S formulation toenhance bioadhesion and permeation to create the 24S formulation, thebioavailability was characterized by a peak plasma level of dopamineagonist within 30 minutes of drug mucosal administration and a plateaulevel of dopamine agonist for the ensuing 2.5 to 4.5 hours ofapproximately >50% of the C_(max) concentration thereby resulting in apeak-plateau bioavailability curve with a 2-3 fold greater C_(max) thanthe 23S formulation.

The 30DL formulation was a tablet that is one half of the 23S and onehalf of the 24S formulation combined together into a single dosage form.This “hybrid” produced a bioavailability much like the 23S, likelybecause the cyclodextrin to dopamine agonist ratio was too low toeffectuate bioadhesion and tissue permeation of the dopamine agonist.

TIME (minutes) Experiment Formu- Dose per Data expressed as % of C_(max)Number lation Animal 0 30 60 90 120 180 1 23S 2 mg 0 100 20 7 7 30 2 23S3 mg 0 62 100 71 29 26 3 24S 2 mg 0 100 57 44 77 n/t 4 24S 2 mg 0 100 8573 92 n/t 5 30DL 3 mg 0 100 11 10 5  4 n/t: not tested

Bioavailability Results of Formulations 32F and 33S

The bioavailability of the 32F formulation was characterized by a peakplasma level of dopamine agonist within 30-90 minutes after mucosaladministration followed by a plateau of plasma dopamine agonist level atapproximately ≧50% C_(max) for up to 3.5 hours. This formulationproduced a bioavailability curve between that of 23S and 24S as expectedfrom the in vitro dissolution profiles and component characteristics ofthese formulations due to the dopamine agonist to bioadhesive ratio (32Fvs. 23S).

The 33S formulation (the 32F formulation plus cyclodextrin) resulted ina bioavailability curve characterized by a peak plasma level of dopamineagonist within 60-90 minutes of mucosal administration and a subsequentplateau plasma level of dopamine agonist of approximately ≧50% ofC_(max) for up to 3.5 hours post Tmax. The 33S formulation alsoincreased the C_(max) by 2-3 fold relative to the 32F formulation. Suchfindings were again consistent with the effects of cyclodextrinincorporation into the formulation as it both delays tablet dissolutionin vitro and increases active agent penetration of tissues in vivo.

Experi- Dose TIME (minutes) ment per Data expressed as % of C_(max)Number Formulation Animal 0 30 90 180 240 300 6 32F 3 mg 0 36 100 23 1817 7 32F 6 mg 0 100 100 78 48 16 8 32F 6 mg 0 100 62 54 34 n/t 9 32F 6mg 0 33 100 99 80 63 10 33S 6 mg 0 60 100 50 66 67 11 33S 6 mg 0 35 10040 33 47 12 33S 6 mg 0 0 100 64 78 n/t 13 33S 6 mg 0 100 72 61 83 100 14 33S 6 mg 0 100 78 78 22 44 n/t: not tested

Formulations 35F and 40SuF Bioavailability Results

The bioavailability of the 35F formulation was characterized by a peakplasma level of dopamine agonist at 180 minutes after its mucosaladministration and a plateau level at approximately >50% C_(max) for thenext 60 minutes with subsequent decline in plasma dopamine agonistlevel. The 35F formulation incorporates both a) an increase in theactive agent to bioadhesive ratio and b) a substitution of citric acidwith ascorbic acid from the 23S formulation. Each of these manipulationsto the 23S formulation was known to delay the in vitro dissolution rateof the active agent as described above in this application; thus, thebioavailability curve of the 35F was consistent with its dissolutioncharacteristics in vitro. Such manipulations within the 35F formulationcan be made to counter any other additions to the 23S formulation thatmay overly accelerate the active agent release and absorption in vivo,and the bioavailability was approximately double that of the 23Sformulation.

The 40SuF formulation was characterized by a rapid peak dopamine agonistlevel within 30 minutes of drug mucosal administration followed by asharp decline (i.e., no plateau level) in the plasma level shortlythereafter. The bioavailability of the 40SuF formulation wasapproximately 3-5 fold greater than that of the 23S formulation. The40SuF formulation may be used to reduce the in vivo T_(max) offormulations that exhibit a delayed in the time to reach T_(max) butotherwise favorable for producing a peak-plateau bioavailability curveand therapeutic effect of dopamine agonist.

Experi- TIME (minutes) ment Dose per Data expressed as % of C_(max)Number Formulation Animal 0 30 90 180 240 300 15 35F 6 mg 0 0 60 100 9524 16 35F 6 mg 0 10 29 83 100 39 17 40SUF 4 mg 0 100 26 49 0  0 18 40SUF4 mg 0 100 6 15 9 n/t n/t: not tested

Example 19 Formulation 34Gel Tested for Mucosal, Transdermal, andSubcutaneous Delivery Routes of Administration

The bioavailability of the 34gel formulation was characterized by a peakin dopamine agonist level within 60-90 minutes after its parenteraladministration (mucosal, transdermal or subcutaneous) followed by aplateau plasma level of approximately ≧50% of C_(max) for up to 1.5 to 3hours thereafter. This formulation exhibits a peak-plateaubioavailability profile whether it was administered mucosally,transdermally, or subcutaneously. Moreover, this formulation ofbromocriptine also produced a highly desirable and surprisinglyeffective improvement in metabolic disorders when administeredparenterally at the appropriate time of day compared to a traditionalformulation of bromocriptine previously employed to treat metabolicdisorders in the same animal model system (see Examples 30-31) Theprevious formulation was unsuitable for pharmaceutical use for severalreasons, including extremely poor stability and untoward side effects atthe administration site, thus, making its therapeutic use impossible.

TIME (minutes) Experiment Formulation, Dose per Data expressed as % ofC_(max) Number route Animal 0 30 60 90 120 180 240 300 19 26Sgel   3 mg0 31 100 100 100 n/t n/t n/t Mucosal 20 34gel 10.8 mg  0 26 100 81 71 4055 67 Transdermal 21 34gel 10.8 mg  0 45 100 79 100 n/t n/t n/tTransdermal 22 34gel SC 3.3 mg 0 54 100 67 92 67 96  8 23 34gel SC 3.3mg 0 100 100 100 100  0 n/t n/t 24 34gel SC 3.3 mg 0 0 0 100 28 50 50 4525 34gel SC 3.3 mg 0 19 34 100 100 27 26 n/t 26 34gel SC 3.3 mg 0 100 6269 81 43 n/t n/t n/t: not tested

Example 20 Blood Levels of Bromocriptine from Parenteral Formulations inan Animal Model of the Obesity, Glucose Intolerance, and InsulinResistance

The plasma level of intraperitoneal administrated bromocriptine in aethanol to water solvent ratio of 30:70, at a dose previouslydemonstrated to reduce the insulin resistant state in Syrian hamsters (5mg/kg), was compared to the plasma levels of bromocriptine in the sameanimal model following parenteral (mucosal, transdermal, orsubcutaneous) administration of the above described formulations of thepresent invention. Mucosal, transdermal, or subcutaneous administrationof 10-20 mg/kg of bromocriptine of the present invention, particularly32F, 33S, 26S, 34Gel, 35F, and 40SuF formulations, to Syrian hamstersresulted in blood levels of bromocriptine similar to those of previousformulations (in the ethanol/water vehicle) administeredintraperitoneally at 5 mg/kg animals. Therefore, it is possible todeliver the formulations of the present invention via parenteral routesto achieve a therapeutically effective dose of dopamine agonist requiredto reduce metabolic disorders in animal models of metabolic disease.

Example 21 In Vivo Effects of 34Gel on Body Weight Gain, Plasma InsulinLevel, Insulin Sensitivity, and Blood Pressure in 16 Week-Old SHR Rats

Sixteen week old male Spontaneous Hypertensive Rats (SHR) were treateddaily with either formula 34Gel with an 30% ethanol vehicle viaparenteral injection at 10 mg/kg body weight (n=100) or 30% ethanolvehicle (n=10) for a period of 7 days at the daily onset of locomotoractivity in these animals (at initial lights off). The measurement ofblood pressure, plasma glucose and insulin levels, and the calculationof insulin sensitivity from the plasma glucose and insulin levels wereconducted. Relative to vehicle controls, 34Gel treatment resulted in areduction in insulin resistance (HOMA-IR) from 12 to 2.65 (FIG. 1), areduction in hyperinsulinemia (from 2.4 to 0.5 ng/ml) (FIG. 2), areduction in systolic and diastolic blood pressure (each by 25 mm Hg)(FIG. 3), a change from baseline in body weight of 50 grams versus again of 18 grams for control animals, (FIGS. 4 and 5), and a reductionin plasma endothelin −1 levels of 47% (FIG. 6). These resultsdemonstrated that parenteral administration of 34Gel at thepre-determined time of day results in a bioavailability curve forbromocriptine with a plasma peak within 90 minutes followed by ≧50% ofC_(max) for the following for at least 60-90 minutes and producesimprovements (reductions) in metabolic disorders in the well establishedSHR rat model of metabolic disease.

Compared to a formulation that does not produce the ideal peal-plateaucurve as described in this application, at an equal dose, parenterallyadministered 34Gel had a greater effect on hyperinsulinemia, insulinresistance, and body weight gain when administered at the same time ofday in the same animal model of metabolie disease (Diabetes 57Suppl 1,A176, 2008). Simultaneous reductions in multiple risk factors forcardiovascular disease such as hyperinsulinemia, insulin resistance,blood pressure, body weight gain, and plasma endothelin-1 level in theSHR rat can be accomplished by timed daily parenteral administration ofa dopamine agonist formulation that produces a peak-plateaubioavailability curve. These results support a role for such therapy inthe treatment (reduction) of cardiovascular disease.

Example 22 Stability of Parenteral Formulations of Bromocriptine

Bromocriptine formulations were placed in low density polyethylenecontainers equipped with a water-absorbing desiccant and maintained at50° C. and 60% relative humidity for 5 days. These formulations werethen prepared for HPLC analysis and analyzed for bromocriptine andbromocriptinine (major degradant of bromocriptine) content againststandard preparations of bromocriptine and bromocriptinine.

The bromocriptinine levels in the 24S, 32F, and 33S formulations wereall less than 2% following their exposure to the 50° C./60% relativehumidity environment for 5 days as tested above. At 4° C., theseformulations exhibit less than 1% bromocriptinine formation.Bromocriptine is extremely labile to heat and moisture and suchconditions generally induce its degradation and resultantly large levelsof bormocriptinine. These bromocriptine formulation stability testresults at 50° C. and 60% relative humidity demonstrate that theseformulations can potentially be stable for long periods of time underroom temperature (25° C.) and humidity conditions.

Discussion of Tablet Formulations

The influence of several excipients upon the dissolution profile of thebuccal dopamine agonist formulation can be readily appreciated bycomparing the dissolution curves for the variousbuccal/sublingual/mucosal formulations of tablets from the 75 through24S formulations below. First, to achieve an in vivo pharmacokineticprofile with a rapid (short) T_(max) (between about 1-90 minutes)followed by a sustained plateau at between 50% to 100% of theC_(max)(for about 60 to 360 minutes) (desired peak-plateau PK profile),a formulation allows for a rapid dissolution (of slope A) (andabsorption) followed by a slower but constant dissolution (of slope <A)(and absorption) (desired release profile). The excipients of Prosolv(microcellulose filler) and Benecel® (bioadhesive, dopamine agonistrelease matrix) slow the (early and late) dissolution rate as theirlevel is increased in the tablet. Contrariwise, the excipients of citricacid and Pharmaburst accelerate the early and overall dissolution rateof the dopamine agonist, respectively. Under these circumstances, wehave demonstrated that adding citric acid and reducing the Benecel®level to the 7S formulation as in 9S increases the overall dissolutionrate of the dopamine agonist while maintaining the desired early fastdissolution followed by a slower constant dissolution. Moreover, if weincrease the Prosolv level in the tablet, the overall dissolution rateis slowed substantially (8S formulation). If cyclodextrin is added tothe 9S formulation as in 10S, one can further improve this desiredrelease profile while enhancing the absorption characteristics of theformulation. If we increase further the citric acid level in the 9Stablet as in the 11S formulation, then the early burst-release of theformulation is markedly enhanced with about 40% released within thefirst 30 minutes followed by a slower but constant release for the next210 minutes. This desired release profile is further improved by theaddition of a cyclodextrin, as in 12S, that also enhances the absorptioncharacteristics of the formulation. If one switches the Explotabdisintegrant for Pharmaburst, the disintegration time is accelerated(from about 15 to 5 minutes). This accelerated disintegration is adesirable characteristic for buccal/sublingual/mucosal tabletadministration that adds to and facilitates patient compliance with use.Also, use of Pharmaburst accelerates the overall dissolution profile ofthe formulation. It can be appreciated that the exact desired releaseprofile conforming to the general characteristics of an early fastrelease followed by a slower sustained release of dopamine agonist canbe achieved by subtle adjustments to those excipients that influence andregulate the kinetics of release (early-fast or secondary sustainedslower release) as described above. The excipients of Prosolv(microcellulose filler) and Benecel® (bioadhesive, dopamine agonistrelease matrix) slow the (early and late) dissolution rate as theirlevel is increased in the tablet. Contrariwise, the excipients of citricacid and Pharmaburst accelerate the early and overall dissolution rateof the dopamine agonist, respectively. The 11S and 12S formulationsexhibit the desired release profiles of the formulation. Furthermore, itwas demonstrated that this formulation allows for very similardissolutions of multiple dopamine agonists even in the circumstance ofsimultaneous combinations of dopamine agonists, such as dopamine D1 andD2 receptor agonists within a single tablet formulation. And, it ispossible to add other metabolic disorder treating agents to thisdopamine agonist formulation. Such additions may or may not requireadjustments to the base formulation to improve or accelerate thedopamine agonist release profile utilizing methods described below.

The 23S and 24S formulations though different from the 11S and 12Sformulations, also exhibit desired release profiles. Relative to 11S and12S formulations, the 23S and 24S formulations, respectively, exhibitthe beneficial characteristic of a reduced disintegration time, thattranslates into increased active agent availability to the absorbingbiological surface during the desired administration window of the day(e.g., mucosal outer layer or cellular membrane) and thereforeincreasing bioavailability during this time. The more rapiddisintegration time also should improve patient compliance with the drugadministration. Moreover, it can be appreciated that by altering theratio of Explotab versus Pharmaburst as well as adjusting the Benecel®and Prosolv levels in the tablet, an intermediate release profile ofdopamine agonist between that of 11S/12S and 23S/24S formulations can beachieved. Such hybrid formulations allow for “fine-tuning” of thedesired formulation of dopamine agonist to produce the desired PKprofile.

Utilizing the 23S and 24S formulations, further investigationsdemonstrated that the bioadhesive level within these tablet formulationsis optimized at a maximum level of bioadhesive to support bioadhesion ofthe active agent that still allows for a quick burst dissolution ofactive agent. Increasing this level (on a percent of total tablet weightbasis) results in a slowing of active agent dissolution time whilereducing has no effect on dissolution time. Therefore, the relativeamounts of bioadhesive agent, active agent and other components of the23S and 24S formulations are optimized to produce the desiredpeak-plateau bioavailability profile and mucosal bioadhesion and tofacilitate tissue absorption. It can further be demonstrated thatincreasing the active agent level within the 23S tablet from 1 to 3 mgper tablet does not alter the dissolution characteristics of the tabletso a range of dosage strengths of parenteral dopamine agonists can bemade of this 23S background formulation. However, upon increasing theactive agent level from 1 to 3 mg per tablet of the 24S formulation, thedissolution profile is accelerated. In formulations (33S) that contain acyclodextrin or other permeabilizing agent in conjunction withbioadhesive, it is possible to accelerate the release of active agent byincreasing its level relative to the cyclodextrin/bioadhesive level.Once again, this new formulation (33S) exhibits several desirablecharacteristics including rapid disintegration of the tablet, presenceof optimal amount of bioadhesive so the active agent is localized to thedesired site of absorption (e.g., reduced gut presentation of activeagent for oral-parenteral administration formulations), quick release ofactive agent followed by a linear slowed release of active agent(peak-plateau dissolution curve) and presence of a permeabilizing agentfor increased tissue absorption of active agent. Within this context,the release profile of the active agent within the tablet can be slowedby switching to a different disintegrant with a more potent bioadhesiveproperty, such as xanthan gum.

In an effort to further accelerate the release of the active agentwithin the formulation, a tablet was constructed with aneffervescent/Pharmaburst combination forming constituent in place of thePharmaburst as the disintegrant, but with the same other ingredients asin the 23S formulation. This particular formulation accelerated thedisintegration time of the tablet and the dissolution time for theactive agent from the tablet relative to the Pharmaburst comparativeformulation (23S). Therefore, it can be appreciated that it is possibleto adjust the disintegration and dissolution time of a tabletformulation with the desired bioavailability profile of a quick-burstpeak followed by a slowed release of active agent by adjusting thedisintegrant of the 11S formulation. If one switches the 11Sdisintegrant (Explotab) to Pharmaburst (as in 23S), the disintegrationand dissolution times are accelerated and if one switches thePharmaburst disintegrant to EfferSoda/Pharmaburst combination (as in40SuF) the disintegration and dissolution times are accelerated yetfurther still. Another method of accelerating the disintegration anddissolution times is the addition of citric acid to the formulation. Andyet a third method of accelerating the disintegration and dissolutiontimes of the formulation is to increase the ratio of active agent tocyclodextrin component of the formulation. Contraiwise, it is possibleto achieve a slower dissolution rate of active agent from theformulation by either adding more cyclodextrin component to theformulation or by switching the citric acid for ascorbic acid within theformulation or by switching the disintegrant/bioadhesive system fromBenecel®-PVP to xanthan gum.

Such formulation preparations achieve the desired peak-plateau releaseprofile of dopamine agonist, are parenteral and eliminate first passmetabolism as well as initial binding to the gastrointestinal dopaminereceptors thereby reducing adverse GI side-effects, can be used fortimed administration of dopamine agonist inasmuch as they are notsustained long-term (e.g., 12-24 hour) release formulations, can beemployed to treat metabolic disease if administered appropriately andthey are stable allowing for practical pharmaceutical use. A basicfinding from these investigations is that alterations made to aparticular formulation's dissolution profile by the above referencedmeans of changing the formulation translates into the same alteration inthe in vivo pharmacokinetic profile of the active agent. For example, ifone accelerates or slows release of active agent in in vitrodissolution, it also accelerates or slows, respectively, the absorptionof active agent in vivo, etc. In total, the above examples provide meansof adjusting the dissolution profile and disintegration times of aformulation while maintaining the desired quick-burst peak dissolutionfollowed by a slower linear-like release of active agent from theformulation. Such above-described methods may be employed to effectuateadjustments in these formulation dissolution and disintegrationparameters that may need to be made to compensate for the effects of anyadditional ingredients, such as other permeabilizing agents used tospeed up or slow down the absorption of the active agent and therebyimpacting the bioavailability profile of the formulation. Moreover, itcan be appreciated that the above examples teach the basic formulationelements and physical science principles, and manipulations to specificingredients within the formulation that may be employed, to constructand prepare other formulations that produce the desired dissolution ofactive agent in vitro and in vivo pharmacokinetic profile of activeagent. In other words, these examples describe methods to adjust thetime and magnitude of the peak quick burst of active agent (dopamineagonist) and also to adjust the slower release phase of dissolution fromthe formulation.

Example 23 Menthol-Enhanced Tablets

Menthol-enhanced tablets (46T) were produced using 33S base formulationwith addition of menthol as a taste enhancer and permeation enhancer.The addition of menthol slowed the drug release rate of the dopamineagonist, bromocriptine, related to the 33S formulation. In vivo,however, the slower dissolution should be countered by the permeationenhancing properties of menthol resulting in the desired peak-plateaubioavailability curve observed with the 33S formulation with the addedbenefit of enhanced absorption of dopamine agonist.

Formulations

46T Excipient Type/Function Amount % mg Bromocriptine API 4.29 750.00Polyvinyl Bioadhesion Enhancer 5.71 1000.00 Pyrrolidone (PVP) Benecel ®Hydroxypropyl Methylcellulose/ 7.36 1300.00 MP814 Bioadhesive/APIRelease Matrix Citric Acid, Solubility, Stability 2.86 500.00 AnhydrousStearic Acid Glidant 1.00 175.00 Pharmaburst Disintegrant, Filler 64.0811215.00 Cavitron 82004 Hydroxypropyl 14.30 2500.00Cyclodextrin/Permeation Enhancer Menthol Permeation enhancer 0.40 70.00Total 100.00 17500.00A 50 mL tube blender was charged with menthol, citric acid. The mixturewas agitated at 300 rev/min for 10 min. Bromocriptine was blended in for10 minutes followed by polyvinyl pyrrolidone. Benecel® was added andblended for 10 min. Caviton was added and blended for 10 minutes. Next,Pharmaburst was added and blended for 30 min. The mixture and separatelyMg stearate was pushed through a 40 mesh sieve and then mixed togetherfor 2 minutes. The dry granulation mixture was pressed into uniformtablets (5 mm die, 70-75 mg) using the TDP press at 4,000 Psi.

Results

Tablet Characteristics 46T Hardness 8.7-9.6 kg Friability PassDisintegration Time 12.0-14.5 min Tablet Uniformity Good

Dissolution Immersion Media: Water.

Dissolution Profile 46T % Cumulative T, min Release 0 0.00 15 12.15 3017.38 60 33.72 120 64.49 180 73.36 240 83.87

Transmucosal Film Formulation Examples Example 24Polyvinylpyrrolidone-Based Transmucosal Film Formulations with anEthanol-Soluble Form of Hydroxypropyl Cellulose (KLUCEL® LF)

Films for transmucosal application of dopamine agonists were preparedwith polyvinylpyrrolidones and polyvinylpyrrolidones-co-polymers. Inorder to enhance the bioadhesive properties of the film, KLUCEL® LF wasused. The polyvinylpyrrolidone-based transmucosal film dosage forms withKLICEL® LF (41Film, 42Film) were prepared as follows:

Formulation

41Film 42Film Excipient Type/Function Amount % mg Amount % mgBromocriptine API 11.45 459.00 8.40 459.00 Kollidon 90F BioadhesionEnhancer 44.60 1787.00 29.37 1604.00 Kollidon VA64 Soluble Binder/FilmForming 6.08 243.70 3.99 218.00 Agent PEG400 Solubility Enhancer 1.4357.30 0.95 52.00 Citric Acid Solubility Enhancer/Stabilizing 11.45459.00 8.40 459.00 Anhydrous Agent KLUCEL ® LF Bioadhesion Enhancer24.98 1001.00 32.88 1796.00 Glcyerol Solubility Enhancer n/a n/a 1.90104.00 Cyclodextrin Solubility Enhancer n/a n/a 14.10 770.00 Total100.00 4007.00 100.00 5462.00 n/a: not addedThe Base Composition was prepared by adding Kollidon 90F, Kollidon VA64,and PEG400 to ethanol in a 2 L graduated Pyrex bottle with a seal screwcap. The ingredients were blended using a Stovall low profile roller atmedium speed for 24 hours at room temperature. The procedure generates atransparent homogenous viscous solution that was stored at 4° C. as astock solution.

KLUCEL® was added to the Base Composition in a 200 mL graduated Pyrexbottle with a seal screw cap. In the case of 42Film, glycerol andcyclodextrin were also added. The ingredients were blended using aStovall low profile roller at medium speed for 24 hours at roomtemperature. The procedure generates a transparent homogeneous viscoussolution that was stored at 4° C. as a stock solution.

The Final Formulation was prepared by dissolving citric acid intoethanol by briefly heating and sonicating the solution. Bromocriptinewas added to the citric acid solution, and the solution was sonicatedfor 5 minutes to produce a while slurry. The slurry was added to theBase Composition and sonicated for 10 minutes to generate a transparentmobile gel that was used for film casting.

A Scotchpack 1022 3M release liner was fixed to a glass plate (about8×12 inches). The liner had been pre-washed with water and detergent tocontrol de-wetting of the film. The 20 mil (0.51 mm, wet thickness)films were cast onto the liner using a GARDCO manual applicator in aFlow Scientific laminar flow box. The film was allowed to set and relaxfor 20 minutes before applying air flow. Air flow was then applied for30 minutes. After about 1 hour, and while the film was still very tackybut well formed, a flow of warm air was applied using an air blower for30 minutes. The air blower was adjusted so that the temperature at thesurface reached about 60-70° C. to minimize heating and possibledecomposition of the bromocriptine. Subsequent drying was achieved byplacing the film in a vacuum desiccator filled with Drierite® for 48hours.

Test Notes:

Film Characteristics 41Film 42Film Total Weight of the Patch 113.70 mg124.10 mg Amount of the Drug  13.00 mg  10.40 mg (based on contentuniformity test)Short-term stability studies (24 hours and 5-10 days) of the patchsamples by HPLC revealed high stability of the bromocriptine and nodecomposition products.Drug Release Immersion Media: Citric Acid Buffer, pH 6.0 (See tablebelow for dissolution profile)

41Film 42Film T, % Cumulative % Cumulative min Release Release 0 0.000.00 5 91.86 72.06 15 105.42 87.43 30 105.98 88.99 45 105.11 88.98

Example 25 Polyvinylpyrrolidone-Based Transmucosal Film Formulationswith High Molecular Weight Hydroxypropyl Methyl Cellulose (Benecel®MP844)

In this example, Benecel® MP844, the highest molecular weight gradehydroxypropyl methyl cellulose, was the bioadhesive used in place ofhydroxypropyl cellulose (KLUCEL® LF. The polyvinylpyrrolidone-basedtransmucosal film dosage forms with Benecel® MP844 (43Film-45Film) wereprepared as follows:

Formulation

43Film 44Film 45Film Excipient Type/Function Amount % mg Amount % mgAmount % mg Bromocriptine API 7.33 410.00 8.92 410.00 9.87 406.00Kollidon 90F Bioadhesion 34.78 1944.00 42.27 1944.00 48.74 2004.00Enhancer Kollidon VA64 Soluble Binder/Film 4.72 264.00 5.75 264.00 6.61272.00 Forming Agent PEG400 Solubility Enhancer 1.11 62.00 1.35 62.001.56 64.00 Citric Acid Solubility 7.33 410.00 8.92 410.00 9.97 410.00Anhydrous Enhancer/Stabilizing Agent Benecel ®Hydroxypropylmethylcellulose/ 44.72 2500.00 32.80 1508.00 18.24 750.00Bioadhesive/API Release Matrix Glcyerol Solubility Enhancer n/a n/a n/an/a 5.01 206.00 Total 100.00 5590.00 100.00 4598.00 100.00 4112.00 n/a:not addedThe Base Composition was prepared by adding Kollidon 90F, Kollidon VA64,and PEG400 to ethanol in a 2 L graduated Pyrex bottle with a seal screwcap. In the case of 45Film, glycerol was also added. The ingredientswere blended using a Stovall low profile roller at medium speed for 24hours at room temperature. The procedure generates a transparenthomogenous viscous solution that was stored at 4° C. as a stocksolution.

The Final Formulation was prepared by dissolving citric acid intoethanol by briefly heating and sonicating the solution. Bromocriptinewas added to the citric acid solution, and the solution was sonicatedfor 5 minutes to produce a while slurry. The slurry was added to theBase Composition and sonicated for 10 minutes to generate a transparentlabile gel. Benecel® was added to the gel and sonicated for 10 minutes.The resulting slurry was homogenized using a Polytron homogenizer for 3minutes at 5,000 rev/min and then immediately used for casting.

A Scotchpack 1022 3M release liner was fixed to a glass plate (about8×12 inches). The liner had been pre-washed with water and detergent tocontrol de-wetting of the film. The 20 mil (0.51 mm, wet thickness)films were cast onto the liner using a GARDCO manual applicator in aFlow Scientific laminar flow box. The film was allowed to set and relaxfor 20 minutes before applying air flow. Air flow was then applied for30 minutes. After about 1 hour, and while the film was still very tackybut well formed, a flow of warm air was applied using an air blower for30 minutes. The air blower was adjusted so that the temperature at thesurface reached about 60-70° C. to minimize heating and possibledecomposition of the bromocriptine. Subsequent drying was achieved byplacing the film in a vacuum desiccator filled with Drierite® for 48hours.

Test Notes:

Film Characteristics 43Film 44Film 45Film Total Weight of the 116.10 mg118.40 mg 111.80 mg Patch Amount of the Drug   8.5 mg  10.56 mg  9.08 mg(based on content uniformity test)Short-term stability studies (24 hours and 5-10 days) of the patchsamples by HPLC revealed high stability of the bromocriptine and nodecomposition products.Drug Release Immersion Media: Citric Acid Buffer, pH 6.0 (See tablebelow for dissolution profile)

43Film 44Film 45Film % % % T, Cumulative Cumulative Cumulative minRelease Release Release 0 0.00 0.00 0.00 5 4.63 18.21 44.00 10 n/a 24.5357.34 15 14.46 26.87 65.45 30 30.99 39.35 83.85 45 42.62 46.68 94.79 6045.56 54.09 97.69 75 57.93 60.20 99.51 90 68.99 63.68 n/a

Example 26 Blood Levels of Bromocriptine from Transmucosal Formulationsin an Animal Model

Transmucosal dosage forms of the present invention (41Film-45Film) wereadministered to Syrian hamsters to demonstrate the in vivobioavailability of the dopamine agonist. The large food storage pouch ofthe Syrian hamster is an ideal biological tissue to study mucosaltransport of compounds and drug formulations. A dose of 4 mgbromocriptine was administered to each Syrian hamster (n=8 per group).Blood samples were taken prior to and at timed intervals between 30 and300 minutes after film administration, and the plasma level ofbromocriptine, was measured. Bromocriptine was extracted from plasma andthe samples were analyzed against standards via HPLC method as describedin Example 18. Bioavailability data are presented as % of C_(max). Thedata represent the best-fit curve acquired per treatment group.

Bioavailability Results of Formulations 41Film-45Film

The bioavailability of the transmucosal film formulation wascharacterized by a bromocriptine peak plasma level within 30 minutes ofdrug mucosal administration with a subsequent reduction in plasma levelsshortly thereafter. The C_(max) values for 41Film, 42Film, 43Film,44Film, and 45Film formulations were 15.2, 36.1, 3.8, 17.6, and 10.7ng/ml of plasma, respectfully. Cyclodextrin type molecules was added to42Film. Cyclodextrin type molecules enhanced the absorption of thedopamine agonist bromocriptine while surprisingly shortening the T_(max)to 60 minutes rather than the 240 minutes exhibited by 41Film, a formulasimilar to 42Film but lacking cyclodextrin type molecules. This resultis surprising because the addition of cyclodextrin type molecules totablet formulations generally slows the release of dopamine agonists.

The transmucosal films of the present invention produced the desireddopamine agonist peak-plateau bioavailability curve in the animal model.In particular, 42Film and 43Film formulations achieved a desiredpeak-plateau bioavailability curve of bromocriptine. Thesebioavailability examples demonstrate that it is possible to manipulate,in a predictive manner, the shape of the bioavailability curve bymanipulating specific components of the film formulation. By alteringthe KLUCEL® to Kollidon ratio or adding cyclodextrin type molecules tothe film formulation (i.e., adjustments made in 42Film formulation), thebioavailability of the dopamine agonist can be adjusted to produce apeak level of dopamine agonist within 90 minutes and a plateau of thedopamine agonist levels from about 60 to 240 minutes in duration. Suchbioavailability curves are useful in treating metabolic diseases.

It is also possible to adjust the in vivo bioavailability of dopamineagonists in film formulations by adding Benecel® to theKLUCEL®/cyclodextrin formulation (42Film) in an effort to slowabsorption resulting in a broadened plateau time following peakabsorption of the dopamine agonist as Benecel® did for 44Film and45Film. Moreover, it is possible to enhance bioavailability and toprovide the desired peak-plateau bioavailability curve of the presentinvention by adding permeation enhancers such as fatty acids andbioadhesives to the present film formulations.

Dose TIME (minutes) Formulation, per Data expressed as % of C_(max)route Animal 0 30 60 90 120 180 240 300 41Film 4 mg 6 21 25 n/t 24 23100 41 42Film 4 mg 7 22 100  85 n/t n/t 51 36 43Film 4 mg 11 38 52 n/t100  80 76 76 44Film 4 mg 8 12  8 13 12 100  82 13 45Film 4 mg 16 42 n/t61 84 n/t 100 71

Example 27 Polyvinylpyrrolidone-Based Transmucosal Film Formulationswith Oleic Acid

Oleic acid was added as a permeation enhancer to the formulation for42Film to form 47Film. The addition of oleic acid did not appreciablychange the drug release properties of 42Film.

Formulation

47Film Excipient Type/Function Amount % mg Bromocriptine API 7.92 457.00Kollidon 90F Bioadhesion Enhancer 27.83 1604.00 Kollidon VA64 SolubleBinder/Film Forming 3.78 218.00 Agent PEG400 Solubility Enhancer 0.9052.00 Citric Acid Solubility Enhancer/Stabilizing 7.96 459.00 AnhydrousAgent KLUCEL ® LF Bioadhesion Enhancer 31.16 1796.00 Glcyerol SolubilityEnhancer 4.51 260.00 Cyclodextrin Solubility Enhancer 13.36 770.00 OleicAcid Permeation Enhancer 2.55 147 Total 100.00 5462.00Formulations were preformed as described for formulation 42Film with theaddition of oleic acid to the final formulation prior to the sonicationstep.

Test Notes:

Film Characteristics 47Film Total Weight of the Patch 120.96 mg Amountof the Drug   9.6 mg (based on content uniformity test)Short-term stability studies (24 hours and 5-10 days) of the patchsamples by HPLC revealed high stability of the bromocriptine and nodecomposition products.Drug Release Immersion Media: Citric Acid Buffer, pH 6.0 (See tablebelow for dissolution profile)

47Film % Cumulative T, min Release 0 0.00 5 82.92 10 89.76 15 94.52 3093.65 60 93.44

Example 28 Polyvinylpyrrolidone-Based Transmucosal Film Formulationswith Lisuride and/or SKF-38393

Films for transmucosal application of lisuride and/or SKF-38393 wereprepared with polyvinylpyrrolidones andpolyvinylpyrrolidones-co-polymers. In order to enhance the bioadhesiveproperties of the film, KLUCEL® LF was used. The drug releasecharacteristics of these new formulations were essentially the same as42Film, which contained bromocriptine as the dopamine agonist.

Formulation

48Film-Lis 49Film-SKF 50Film-Lis/SKF Excipient Type/Function Amount % mgAmount % mg Amount % mg Lisuride API 2.76 148 n/a n/a 2.52 141.00SKF-38393 API n/a n/a 4.87 252.00 4.38 214.00 Kollidon 90F BioadhesionEnhancer 29.90 1604.00 31.04 1604.00 28.67 1604.00 Kollidon VA64 SolubleBinder/Film 4.06 218.00 4.22 218.00 3.90 218.00 Forming Agent PEG400Solubility Enhancer 0.97 52.00 1.01 52.00 0.92 52.00 Citric AcidSolubility 8.54 459.00 2.09 108.00 6.38 357.00 AnhydrousEnhancer/Stabilizing Agent KLUCEL ® LF Bioadhesion Enhancer 33.491796.00 34.75 1796.00 32.11 1796.00 Glcyerol Solubility Enhancer 5.89316 7.12 368.00 7.41 415.00 Cyclodextrin Solubility Enhancer 14.35770.00 14.90 770.00 13.76 770.00 Total 100.00 4007.00 100.00 5462.00100.00 5462.00 n/a: not addedFormulations were preformed as described for formulation 42Film excepteither lisuride, SKF-38393, or both were added in place ofbromocriptine.

Test Notes:

Film 49Film- 50Film- Characteristics 48Film-Lis SKF Lis/SKF Total Weightof the 98.50 mg 127.60 mg 176.70 mg Patch Amount of the Drug  2.60 mg 6.22 mg  4.45 mg (based on content uniformity test)Short-term stability studies (24 hours and 5-10 days) of the patchsamples by HPLC revealed high stability of the bromocriptine and nodecomposition products.Drug Release Immersion Media: Citric Acid Buffer, pH 6.0 (See tablebelow for dissolution profile)

48Film-Lis 49Film-SKF 50Film- % % Lis/SKF % T, Cumulative CumulativeCumulative min Release Release Release 0 0.00 0.00 0.00 5 86.64 93.1243.43 10 88.79 100.3 79.57 15 91.27 101.47 93.05 30 96.28 101.32 93.2660 95.72 101.91 94.04

Example 29 Subcutaneous Oil-Based Formulation

50 mg of bromocriptine was passed through a 40 mesh sieve, placed into a20 mL scintillation vial and suspended in 1 g of polysorbate 80. thesuspension was sonicated for 15 minutes with periodic manual shaking ofthe vial in order to allow for material attached to the walls to bedissolved. Bromocriptine gradually dissolved into a clear solution, withfew residual aggregates. To this solution, sesame oil was added and thesolution was sonicated for 10 minutes. A resulting translucenthomogeneous emulsion of bromocriptine (about 0.05%) could be used forparenteral application once passed through a sterilizing filter.

It is recommended to shake it well immediately before administration. Itwill require administration of about 100 mg of the emulsion to deliver0.5 mg of bromocriptine. Based on the literature density data of 0.9g/cm³ for sesame oil and 1.08 g/cm³ of polysorbate 80, this willcorrespond to a volume of approximately 110 μl. To this preparation canbe added citric acid to enhance the stability of the dopamine agonistand its absorption into the circulation.

The composition VS-49SC contains about 10% of polysorbate 80.

Stability Studies

Immediately after the preparation, using microscopy, we did not observeany droplets of separated phases of oil and polysorbate 80. The limit ofthe observation was around 5 microns. However, after 2-3 daysunperturbed at room temperature, the emulsion displays separated layersof two components. Apparent homogenization can be achieved by vigorousmanual shaking or sonication.

The present invention is not to be limited in scope by the specificembodiments described herein. Indeed various modifications of theinvention in addition to those described herein will be apparent tothose skilled in the art from the foregoing description and theaccompanying Figures. Such modifications are intended to fall within thescope of the appended claims.

It is further to be understood that all values are approximate and areprovided for description. All references cited and discussed in thisspecification are incorporated herein by reference in their entirety andto the same extent as if each reference was individually incorporated byreference.

1. A stable parenteral dosage form comprising at least one dopamineagonist and a pharmaceutically acceptable excipient, and exhibiting apharmacokinetic profile comprising: a) a T_(max) at about 1 to about 90minutes after administration of the parenteral dosage form; b) a plasmadrug concentration plateau of at least 50% C_(max) for a duration ofabout 90 to about 360 minutes.
 2. The parenteral dosage form of claim 1exhibiting a pharmacokinetic profile wherein at least about 90% of thedopamine agonist is cleared from plasma within about 240 to about 480minutes of said plasma drug concentration plateau.
 3. The parenteraldosage form of claim 1 wherein said T_(max) is about 5 to about 90minutes after administration of the parenteral dosage form.
 4. Theparental dosage form of claim 1 exhibiting a pharmacokinetic profilewherein said T_(max) is about 5 to about 90 minutes after administrationof the dosage form and said plateau comprises a post-C_(max) levelcomprising about one-half C_(max) within about 30 to about 150 minutesof T_(max).
 5. The parental dosage form of claim 1 exhibiting apharmacokinetic profile wherein said T_(max) is about 5 to about 90minutes after administration of the dosage form and said plateaucomprises a post-C_(max) level comprising about one-half C_(max) withinabout 90 to about 360 minutes of T_(max).
 6. The parenteral dosage formof claim 1 comprising a D₁ dopamine agonist, a D₂ dopamine agonist, or acombination of a D₁ dopamine agonist and a D₂ dopamine agonist.
 7. Theparenteral dosage form of claim 1 wherein said at least one dopamineagonist comprises at least one of an ergot derivative or a non-ergotderivative.
 8. The parenteral dosage form of claim 6 wherein said D₂dopamine agonist is selected from the group consisting of bromocriptine,lisuride, terguride, dihydroergotoxine (hydergine), ropinorole,piribedil, apomorphine, quinelorane, talipexole, ergot alkaloidderivatives, and ergoline derivatives.
 9. The parenteral dosage form ofclaim 8 wherein said ergot alkaloid derivatives are selected from thegroup consisting of dihydro-alpha-ergocriptine,dihydro-alpha-ergotoxine, ergocornine, and 9,10-dihydroergocornine. 10.The parenteral dosage form of claim 1, wherein said one or more dopamineagonists comprises bromocriptine.
 11. The parenteral dosage form ofclaim 6 wherein said D₁ agonist is selected from the group consisting ofdopamine, apomorphine, fenoldapam, SKF38393, SKF 75670, SKF 82957, SKF81297, SKF 82958, SKF 82598, A77636, A68930, and benzazepine analogs.12. The parenteral dosage form of claim 1 in the form of a nasal,sublingual, buccal, transdermal, or subcutaneous dosage form.
 13. Theparenteral dosage form of claim 1 comprising a total of about 0.02 toabout 50.0 mg of said at least one dopamine agonist.
 14. A method oftreating a metabolic disorder or key element thereof, comprisingadministering to a subject in need of such treatment the parenteraldosage form of claim 1, to treat said metabolic disorder or key elementthereof.
 15. The method of claim 14 wherein said metabolic disorder orkey element thereof is selected from the group consisting of type 2diabetes, prediabetes, metabolic syndrome, insulin resistance,hyperinsulinemia, cardiovascular disease, obesity, elevated plasmanorepinephrine, elevated cardiovascular-related inflammatory factors orpotentiators of vascular endothelial dysfunction, hyperlipoproteinemia,atherosclerosis, hyperphagia, hyperglycemia, hyperlipidemia,hypertension, high blood pressure, metabolic syndrome, elevated plasmanorepinephrine, elevated cardiovascular-related inflammatory factors,and hypertension.
 16. The method of claim 14, wherein said key elementis selected from the group consisting of impaired fasting glucose,impaired glucose tolerance, increased waist circumference, increasedvisceral fat content, increased fasting plasma glucose, increasedfasting plasma triglycerides, increased fasting plasma free fatty acids,decreased fasting plasma high density lipoprotein level, increasedsystolic or diastolic blood pressure, increased plasma postprandialtriglyceride or free fatty acid levels, increased cellular oxidativestress or plasma indicators thereof, increased circulatinghypercoagulative state, arteriosclerosis, coronary artery disease,peripheral vascular disease, congestive heart failure, renal diseaseincluding renal insufficiency, hepatic steatosis and cerebrovasculardisease.
 17. The method of claim 14, wherein the subject is sufferingfrom at least one condition selected from type 2 diabetes, obesity,prediabetes, metabolic syndrome, and elevated cardiovascular-relatedinflammatory factors.
 18. The method of claim 14 which comprisesadministering said parental dosage form to reduce elevatedcardiovascular-related inflammatory factors or cardiovascular disease orkey elements of cardiovascular disease.
 19. The method of claim 14,wherein the parenteral dosage form is administered as a single dailydose comprising a total of about 0.02 to about 50.0 mg of said at leastone dopamine agonist.
 20. The method of claim 14 wherein the parenteraldosage form is administered at a pre-determined time of day.
 21. Themethod of claim 20 wherein said pre-determined time of day is at aboutthe natural daily peak in the circadian rhythm of central dopaminergicneuronal activity in the circadian rhythm of plasma prolactin level in ahealthy individual of the same species and sex as said subject in need.22. The method of claim 21, wherein the parental dosage form isadministered from about 0400 to about 1200 hours.
 23. The method ofclaim 14, wherein said dosage form comprises bromocriptine.
 24. A methodof reducing elevated plasma norepinephrine levels comprisingadministering to a subject in need thereof the parenteral dosage form ofclaim 1, to reduce said elevated plasma norepinephrine levels.
 25. Theparenteral dosage form of claim 1 further comprising ananti-hypertensive agent, anti-inflammatory agent, anti-coagulativeagent, anti-hypercholesterolemic agent, anti-hypertriglyceridemic agent,anti-hyperglycemic agent or HMGCoA reductase inhibitor.
 26. A method oftreating a metabolic disorder or key element thereof, comprisingadministering to a subject in need of such treatment the parenteraldosage form of claim 25, to treat said metabolic disorder or key elementthereof.
 27. The method of claim 26 wherein the parenteral dosage formis administered at a pre-determined time of day.
 28. The method of claim27 wherein said pre-determined time of day is at about the natural dailypeak in the circadian rhythm of central dopaminergic neuronal activityin the circadian rhythm of plasma prolactin level in a healthyindividual of the same species and sex as said subject in need.
 29. Themethod of claim 28, wherein the parental dosage form is administeredfrom about 0400 to about 1200 hours.
 30. The method of claim 25, whereinsaid dosage form comprises bromocriptine.
 31. A sublingual tablet dosageform comprising by weight: 0.5-20% active agent, 3-50% release matrix,0.5-10% glidant, a solubility enhancer in an amount up to 70%, abioadhesion enhancer in an amount up to 25%, a permeation enhancer in anamount up to 30%, a disintegrant in an amount up to 95%, a filler in anamount up to 95%, and an effervescent in an amount up to 65%.
 32. Thesublingual tablet dosage form of claim 31, comprising by weight: 0.5-10%active agent, 3-20% release matrix, 0.5-5% glidant, a solubilityenhancer in an amount up to 30%, a bioadhesion enhancer in an amount upto 10%, a permeation enhancer in an amount up to 20%, a disintegrant inan amount up to 85%, a filler in an amount up to 80%, and a effervescentin an amount up to 45%.
 33. The sublingual tablet dosage form of claim31, comprising by weight: 0.5-5% active agent, 7-15% release matrix,0.5-2.5% glidant, 2-20% solubility enhancer, 2-8% bioadhesion enhancer,a permeation enhancer in an amount up to 15%, a disintegrant in anamount up to 82%, a filler in an amount up to 75%, and an effervescentin an amount up to 45%.
 34. The sublingual tablet dosage form of claim31, wherein the dosage form comprises by weight: 0.5-5% dopamineagonist, 2-15% polyvinylpyrrolidone, 3-20% hydroxypropylmethylcellulose,3-25% sodium starch glycolate and sodium carboxymethyl starch, 3-25%ProSolv, 0.5-10% citric acid, 0.5-5% steric acid, 40-80% mannitol, andoptionally 5-30% cyclodextrin type molecules.
 35. The sublingual tabletdosage form of claim 31, wherein the dosage form comprises by weight:0.5-4.5% dopamine agonist, 2-6.5% polyvinylpyrrolidone, 3-10%hydroxypropylmethylcellulose, 1-6% citric acid, 0.5-5% steric acid,60-90% Pharmaburst, and optionally 5-30% cyclodextrin type molecules.36. The sublingual tablet dosage form of claim 31, wherein the dosageform comprises by weight: 1-6% dopamine agonist, 2-10%polyvinylpyrrolidone, 3-10% hydroxypropylmethylcellulose, 1-10% citricacid, 0.5-5% steric acid, 60-90% Pharmaburst, and optionally 5-30%cyclodextrin type molecules.
 37. The sublingual tablet dosage form ofclaim 31, wherein the dosage form comprises by weight: 0.5-5.0% dopamineagonist, 5-25% polyvinylpyrrolidone, 5-35% hydroxypropylmethylcellulose,10-40% citric acid, 0.5-5% steric acid, 3-25% Pharmaburst, and 10-65%sodium bicarbonate.
 38. A transdermal gel dosage form comprising byweight: 1-3% active agent, 5-95% solvents, 1-30% thickener, 0.5-10%stabilizer, and a bioadhesive in an amount up to 35%.
 39. Thetransdermal gel dosage form of claim 38, wherein the dosage formcomprises by weight: 0.5-10% dopamine agonist, 5-40% polyethyleneglycol, 45-85% glycerol, 3-25% silica, and 0.5-5% citric acid.
 40. Thetransdermal gel dosage form of claim 38, wherein the dosage formcomprises by weight: 0.5-10% dopamine agonist, 5-40% polyethyleneglycol, 45-85% glycerol, 3-25% silica, 0.5-5% citric acid, 1-15%hydroxypropylmethylcellulose, 0.5-15% polyvinylpyrrolidone.
 41. Atransmucosal film dosage form comprising by weight: 5-20% active agent,1-10% film forming agent, 5-20% stabilizing enhancer, 10-95% bioadhesionenhancers, 0-50% solubility enhancers, and optionally 1-10% oleic acid.42. The transmucosal film dosage form of claim 41, wherein the dosageform comprises by weight: 2-20% dopamine agonist, 10-55% Kollidon 90F,0.5-10% Kollidon VA64, 0.3-5% polyethylene glycol, 10-55%hydroxypropylcellulose, 0.5-10% glycerol, 3-30% cyclodextrin, 2-20%citric acid, and optionally 1-5% oleic acid.
 43. A subcutaneous dosageform comprising by weight: 0.01-0.10% active agent, 5-20% emulsifyingagent, and 80-95% oil.
 44. The subcutaneous dosage form of claim 43,wherein the dosage form comprises by weight: 0.01-0.1% bromocriptine,5-10% polysorbate 80, and 90-95% sesame seed oil.
 45. The dosage form ofany of claims 31-33, 38, 41, or 43, wherein the active agent is one ormore dopamine agonists.
 46. (canceled)
 47. (canceled)
 48. The dosageform of any of claims 31-44, further comprising a cholesterol-loweringagent or an anti-hypertensive agent.
 49. (canceled)
 50. (canceled) 51.(canceled)
 52. A method of treating a metabolic disorder or key elementthereof, comprising administering to a subject in need of such treatmentthe dosage form of any of claims 31-44, to treat said metabolic disorderor key element thereof. 53-62. (canceled)